Novel crystalline forms of the anti-cancer compound zd1839

ABSTRACT

The invention concerns certain crystalline solvates and hydrates of the compound of the Formula (I) which is known inter alia by way of the code number ZD1839. In particular, the invention concerns a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD1839 trihydrate. The invention further concerns processes for the preparation of these solvates and the trihydrate and for their conversion back to the compound ZD1839, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use the production of an anti-proliferative effect in a warm-blooded animal such as man.

The present invention relates to particular crystalline forms of apharmaceutical compound, to processes for their preparation, to theiruse in the purification of that pharmaceutical compound, topharmaceutical compositions comprising them and to their use in therapy.

International Patent Application WO 96/33980 discloses within Example 1the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline.That compound is an inhibitor of the epidermal growth factor receptor(EGFR) family of tyrosine kinase enzymes such as erbB1 and possessesanti-proliferative activity such as anti-cancer activity and,accordingly, is useful in methods of treatment of proliferative diseasesuch as cancer in the human or animal body.

That compound has the structure of the Formula I

and is now known as Iressa (registered trade mark) and gefitinib (UnitesStates Adopted Name) and by way of the code number ZD1839 and ChemicalAbstracts Registry Number 184475-35-2.

The subject matter of Example 1 of International Patent Application WO96/33980 discloses the preparation of the compound of the Formula Iwhich, after purification by column chromatography on silica using a 4:1mixture of ethyl acetate and methanol as eluent and recrystallisationfrom toluene, is stated to have m.p. 119-120° C. The subject matter ofExample 10 of that patent application discloses an alternative syntheticroute to the compound of the Formula I that involves purification bycolumn chromatography on silica using a 9:1 mixture of methylenechloride and methanol as eluent and recrystallisation from toluene.There is no specific disclosure in either of Examples 1 and 10 ofInternational Patent Application WO 96/33980 whether the compound of theFormula I is crystalline or amorphous. Furthermore, there is no specificdisclosure in those examples whether the compound may exist in asolvated form.

It is stated in International Patent Application WO 96/33980 that thequinazoline derivatives disclosed therein can exist in solvated as wellas unsolvated forms such as, for example, hydrated forms and that theinvention therein encompasses all such solvated forms which possessanti-proliferative activity. However, no particular hydrated forms aredisclosed and no particular solvates are disclosed.

We have now found that certain forms of the compound of Formula Iincluding certain solvates thereof are crystalline materials thatpossess advantageous properties.

A particular crystalline form of a compound may have physical propertiesthat differ from those of any other crystalline or amorphous form andsuch properties may influence markedly the chemical and pharmaceuticalprocessing of the compound, particularly when the compound is preparedor used on a commercial scale. For example, each crystal form of acompound may show differences in physical properties such as crystallinesize and shape, melting point, density, hygroscopicity and stability.Such differences may alter the mechanical handling properties of thecompound (such as the flow characteristics of the solid material) andthe compression characteristics of the compound. Different crystallineforms of a compound may have different thermodynamic stabilities. Ingeneral, the more stable form, for example the more stable polymorphicform, is the more suitable physical form for formulation and processingon a commercial scale.

For example, problems could arise in the processing of a less stableform, for example a less stable polymorph. Compression forces such asthose used in tabletting processes could convert some of a less stableform into a more stable form resulting in growth of crystals of the morestable form in the formulated product. This could be undersirable sinceany such crystallisation process could disrupt the integrity of thetablet resulting in a friable tablet of decreased tablet strength. Inaddition, if a variable mixture of two such forms were to be present,the dissolution rate and bioavailability of the active compound(s) couldbe variable as, for example, each form could have a different particlesize. It is well known that particle size can affect the dissolutionrate and bioavailability of a pharmaceutically-active compound. Thequality of the product could therefore be affected undesirably.

Furthermore it is preferred that pharmaceutical compounds in the form ofcapsules or tablets are prepared using the most stable form, for examplethe most stable polymorph, and not a metastable phase or mixture offorms as there is a requirement to demonstrate to the appropriateregulatory authorities that the composition of the compound iscontrolled and stable. If a thermodynamically less stable form, forexample a less stable polymorph, were resent alone or in admixture witha thermodynamically more stable form in a tablet, it would be verydifficult to control the composition of the tablet, for example thepolymorphic composition of the tablet, since the quantity of the morethermodynamically stable form could end to increase on storage.

Accordingly, these factors may have an impact on solid phase, tablet orcapsule formulations of the compound and on suspension formulationsthereof.

A study of the properties of the compound of the Formula I has beenperformed to discover whether polymorphism and/or solvate formation ispossible. A wide range of recrystallisation solvents of variouspolarities was investigated. From most of these solvents, only a singlenon-solvated, crystalline form of the compound of the Formula I wasobtained which is designated hereinafter as Form 1 ZD1839 polymorph. Twosolvates were also identified as of interest. The first solvate occurredin the presence of methanol and this is designated hereinafter as Form 2ZD1839 MeOH solvate and the second solvate occurred with dimethylsulphoxide and this is designated hereinafter as Form 3 ZD1839 DMSOsolvate. We have also found a trihydrate, designated hereinafter as form5 ZD1839 trihydrate.

In particular, it has now been found that Form 3 ZD1839 DMSO solvate iscrystalline and that, surprisingly, that form has advantageousproperties.

Further, we have discovered that Form 3 ZD1839 DMSO solvate is unusualin that it possesses a crystalline physical form that is easily isolatedand is also very stable. Moreover, this solvate may readily be preparedon a commercial scale at a high level of purity and in high yield. Inaddition this solvate may readily be converted into the compound ofFormula I, in particular into the compound of Formula I in the form ofForm 1 ZD1839 polymorph. Overall, the inclusion of the steps of DMSOsolvate preparation, purification thereof and conversion back to thecompound of Formula I is beneficial in terms of yield and purity of thecompound of Formula I.

According to one aspect of the present invention there is provided acrystalline form of the compound of the Formula I substantially in theform of Form 3 ZD1839 DMSO solvate.

According to a further aspect of the present invention there is provideda crystalline form of the compound of the Formula I substantially in theform of Form 3 ZD1839 DMSO solvate and substantially free of any otherZD1839 solvate or any Form 1 ZD1839 polymorph.

When it is stated that the present invention relates to a crystallineform of the compound of the Formula I, the degree of crystallinity asdetermined by X-ray powder diffraction data is conveniently greater thanabout 60%, more conveniently greater than about 80%, preferably greaterthan about 90% and more preferably greater than about 95%. Mostpreferably, the degree of crystallinity as determined by X-ray powderdiffraction data is greater than about 98%.

When it is stated that the present invention relates to Form 3 ZD1839DMSO solvate, the molar ratio of ZD1839 to dimethyl sulphoxide solventmolecule is in the range 3:1 to 1:3, preferably in the range 2.1 to 1:2,more preferably about 1 equivalent of ZD1839 to about 1 equivalent ofDMSO.

When it is stated that the present invention relates to a crystallineform of the compound of the Formula I substantially in the form of Form3 ZD 1839 DMSO solvate, this means that at least 80% of the compound ofthe Formula I is in the form of Form 3 ZD1839 DMSO solvate. Preferablyat least 90% and, in particular, at least 95% of the compound of theFormula I is in the form of Form 3 ZD1839 DMSO solvate. More preferablyat least 98% of the compound of the Formula I is in the form of Form 3ZD1839 DMSO solvate.

When it is stated that the invention relates to Form 3 ZD1839 DMSOsolvate substantially free of any other ZD1839 solvate or any Form 1ZD1839 polymorph, this means that at least 80% of the compound of theFormula I is in the form of Form 3 ZD1839 DMSO solvate and less than 20%of the compound of the Formula I is in the form of any other ZD1839solvate or any Form 1 ZD1839 polymorph. Preferably at least 90% and, inparticular, at least 95% of the compound of the Formula I is in the formof Form 3 ZD1839 DMSO solvate.

Further, we have discovered that Form 2 ZD1839 MeOH solvate alsopossesses a crystalline physical form that is easily isolated and it isof sufficient stability readily to be prepared on a commercial scale ata high level of purity and in high yield. In addition this solvate maybe converted into the compound of Formula I.

According to a further aspect of the present invention there is provideda crystalline form of the compound of the Formula I substantially in theform of Form 2 ZD1839 MeOH solvate.

According to a further aspect of the present invention there is provideda crystalline form of the compound of the Formula I substantially in theform of Form 2 ZD1839 MeOH solvate and substantially free of any otherZD1839 solvate or any Form 1 ZD1839 polymorph.

When it is stated that this aspect of the present invention relates to acrystalline form of the compound of the Formula I, the degree ofcrystallinity as determined by X-ray powder diffraction data isconveniently greater than about 60%, more conveniently greater thanabout 70%, preferably greater than about 80% and more preferably greaterthan about 90%. Most preferably, the degree of crystallinity asdetermined by X-ray powder diffraction data is greater than about 95%.

When it is stated that the present invention relates to Form 2 ZD1839MeOH solvate, the molar ratio of ZD1839 to methanol solvent molecule isin the range 6:1 to 1:3, preferably in the range 4:1 to 1:2, morepreferably about 2 equivalents of ZD1839 to about 1 equivalent ofmethanol, i.e. the material can be approximately a hemi-solvate.

When it is stated that the present invention relates to a crystallineform of the compound of the Formula I substantially in the form of Form2 ZD1839 MeOH solvate, this means that at least 80% of the compound ofthe Formula I is in the form of Form 2 ZD1839 MeOH solvate. Preferablyat least 90% and, in particular, at least 95% of the compound of theFormula I is in the form of Form 2 ZD1839 MeOH solvate. More preferablyat least 98% of the compound of the Formula I is in the form of Form 2ZD1839 MeOH solvate.

When it is stated that the invention relates to Form 2 ZD1839 MeOHsolvate substantially free of any other ZD1839 solvate or any Form 1ZD1839 polymorph, this means that at least 80% of the compound of theFormula I is in the form of Form 2 ZD1839 MeOH solvate and less than 20%of the compound of the Formula I is in the form of any other ZD1839solvate or any Form 1 ZD1839 polymorph. Preferably at least 90% and, inparticular, at least 95% of the compound of the Formula I is in the formof Form 2 ZD1839 MeOH solvate.

Certain other solvates of the compound of Formula I may be obtained butthese do not possess crystalline physical forms that are both easilyisolated and stable. For example, when the compound of Formula I wasallowed to crystallise by the slow evaporation of a solvent systemcomprising a particular mixture of isopropanol and water, thecrystalline solid obtained comprised an isopropanolate solvate that alsocarried two equivalents of water. However, for example, when thecompound of Formula I was recrystallised in a solvent system comprisinga mixture of isopropanol and water, under some conditions thecrystalline solid obtained comprised not only Form 1 ZD1839 polymorphbut also a further material which is believed to be a metastableanhydrate ZD1839 polymorphic form.

In contrast, from many solvents only a single non-solvated, crystallineform of the compound of the Formula I was obtained which is designatedas Form 1 ZD1839 polymorph. We have discovered that Form 1 ZD1839polymorph possesses a crystalline physical form that is easily isolatedand is also highly stable such that this polymorph may readily beprepared on a commercial scale at a high level of purity and in highyield. There is therefore provided a crystalline form of the compound ofthe Formula I substantially in the form of Form 1 ZD1839 polymorph,preferably substantially free of any other polymorphic form of ZD1839 orof any ZD1839 solvate or hydrate.

Form 1 ZD1839 polymorph has a melting point in the range of about 194°C. to 198° C. it was not disclosed in International Patent ApplicationWO 96/33980 that the compound of the Formula I could exist in apolymorphic form of m.p. about 195° C., nor was a process disclosed forpreparing that polymorph substantially free of any other polymorphicform of ZD1839 or of any ZD1839 solvate. It was disclosed inInternational Patent Application WO 96/33980 that the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,now known by way of the code number ZD1839, had m.p. 119-120° C. It isbelieved that the material obtained at that time may have been themetastable anhydrate polymorphic form of ZD1839.

When it is stated that a crystalline form of the compound of the FormulaI in the form of Form 1 ZD1839 polymorph may be obtained, the degree ofcrystallinity as determined by X-ray powder diffraction data isconveniently greater than about 60%, more conveniently greater thanabout 70%, preferably greater than about 80% and more preferably greaterthan about 90%. Most preferably, the degree of crystallinity asdetermined by X-ray powder diffraction data is greater than about 95%.

When it is stated that a crystalline form of the compound of the FormulaI may be obtained that is substantially in the form of Form 1 ZD1839polymorph, this means that at least 80% of the compound of the Formula Iis in the form of Form 1 ZD1839 polymorph. Preferably at least 90% and,in particular, at least 95% of the compound of the Formula I is in theform of Form 1 ZD1839 polymorph. More preferably at least 98% of thecompound of the Formula I is in the form of Form 1 ZD1839 polymorph.

When it is stated that Form 1 ZD1839 polymorph may be obtainedsubstantially free of any other polymorphic form of ZD1839 or of anyZD1839 solvate, this means that at least 80% of the compound of theFormula I is in the form of Form 1 ZD1839 polymorph. Preferably at least90% and, in particular, at least 95% of the compound of the Formula I isin the form of Form 1 ZD1839 polymorph.

We have also surprisingly found that the compound of Formula I can existas a trihydrate (hereinafter Form 5 ZD1839 trihydrate) and that Form 5ZD1839 trihydrate possesses advantageous properties.

Form 5 ZD1839 trihydrate is a stable form of the compound of Formula IIn particular, Form 5 ZD1839 trihydrate is very stable in the presenceof water. For example, when Form 5 ZD1839 trihydrate is prepared as anaqueous suspension the resulting suspension is stable, whereas aqueoussuspensions prepared using other forms of the compound of Formula I areprone to convert to Form 5 ZD1839 trihydrate during storage. In the caseof aqueous suspensions of the compound of Formula I this can beproblematic because the conversion of a less thermodynamically stableform to the Form 5 ZD1839 trihydrate can result in the growth of largecrystals of the Form 5 ZD1839 trihydrate, thereby altering the particlesize distribution in the suspension. This may result in the suspensionbecoming unstable due to the sedimentation of the crystals which maygrow as a result of the conversion from a less stable form to the morestable Form 5 ZD1839 trihydrate. Furthermore, if a variable mixture oftwo such forms of the compound of Formula I were to be present, thedissolution rate and bioavailability of the active compound(s) could bevariable as a result of the different characteristics of the two forms.

Form 5 ZD1839 trihydrate may exhibit other physical properties such ascrystalline size and shape, melting point, density and hygroscopicitythat differ when compared to known forms of the compound of Formula I.Such differences may provide advantageous handling properties of thecompound such as improved flow characteristics of the solid materialand/or improved filtration during manufacture. Such advantages mayprovide improved formulation and processing of the compound of Formula Ion a commercial scale. In particular the small needle or rod-likecrystal habit of the Form 5 ZD1839 trihydrate provides a material withadvantageous filtration properties and drying characteristics.

Moreover, Form 5 ZD1839 trihydrate may readily be prepared on acommercial scale at a high level of purity and in high yield. Inaddition Form 5 ZD1839 trihydrate can be readily converted into the Form1 ZD1839 polymorph. The preparation of Form 5 ZD1839 trihydrate,purification thereof and conversion back to the Form 1 ZD1839 polymorphis beneficial in terms of yield and purity of the compound of the Form 1ZD1839 polymorph, a form which is particularly suitable for use in solidformulations such as tablet and capsule formulations containing thecompound of Formula I.

According to a further aspect of the invention there is provided4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinetrihydrate (Form 5 ZD1839 trihydrate).

According to a further aspect of the invention there is provided Form 5ZD1839 trihydrate which is substantially free of any other ZD1839solvate or ZD1839 polymorph such as for example Form 1 ZD1839 polymorph,Form 2 ZD1839 MeOH solvate or Form 3 ZD1839 DMSO.

The Form 5 ZD1839 trihydrate according to the present invention ishighly crystalline. By “highly crystalline” is meant that the degree ofcrystallinity, as determined by X-ray powder diffraction data, isconveniently greater than about 60%, more conveniently greater thanabout 80%, particularly greater than about 90% and more particularlygreater, than about 95%.

When it is stated that the present invention relates to Form 5 ZD1839trihydrate, the molar ratio of ZD1839 to water is in the range 1:2.5 to1:3.5, more particularly approximately 1:3.

When it is stated that the invention relates to Form 5 ZD1839 trihydratesubstantially free of any other ZD1839 solvate or any other ZD1839polymorph, this means that at least 80% of the compound of the Formula Iis in the form of Form 5 ZD1839 trihydrate and less than 20% of thecompound of the Formula I is in the form of any other ZD1839 solvate orany other ZD1839 polymorph. Particularly at least 90% and, inparticular, at least 95% of the compound of the Formula I is in the formof Form 5 ZD1839 trihydrate.

Samples of the particular crystalline forms of the compound of theFormula I were analysed using a combination of X-Ray Powder Diffraction(hereinafter XRPD) analysis, Differential Scanning Calorimetry(hereinafter DSC), Thermal Gravimetric Analysis (hereinafter TGA),Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy,Near Infrared (NIR) spectroscopy, solid state nuclear magnetic resonancespectroscopy and/or water content determination by Karl Fischeranalysis.

X-ray diffraction data were obtained using Siemens D5000 equipment, theuse of which is described in more detail hereinafter. It will beappreciated that different equipment and/or conditions may result inslightly different data being generated, for example there may bevariation in the location and relative intensities of the peaks. Inparticular, the intensities of peaks measured using XRPD may vary as aresult of particle size and shape because of the effects of the packingof the crystalline particles into XRPD mounts. Such packing effects arewell known in the art and are often referred to as the “preferredorientation” effect. Preferred orientation in the specimen influencesthe intensities of various reflections so that some are more intense andothers less, compared to that which would be expected from a completelyrandom sample. Therefore, intensity variations can occur for the samesample, which are dependent on, for example, the particle size andshape. The preferred orientation effect is especially evident forneedle-like or plate-like crystals when size reduction yields finerneedles or platelets. As a result polymorphic forms are most reliablycharacterised primarily by peak positions in the X-ray diffractogram.These effects as well as methods for standard X-ray diffraction analysiscan be found in, for example, Bunn, C. W. (1948), ChemicalCrystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L.E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York.Hence the figures quoted are not to be taken as absolute values.

The compound of Formula I in the form of Form 1 ZD1839 polymorph has theX-ray diffraction pattern shown in FIG. 1 hereinafter havingcharacterising peaks [on the 2 theta (θ) scale] at about 7.0, 11.2,15.8, 19.3, 24.0 (largest peak) and 26.3°.

Melting points and TGA were determined using Perkin Elmer Pyris 1DSC/TGA equipment, the use of which is described in more detailhereinafter. It will be appreciated that alternative readings of meltingpoint may be given by other types of equipment or by using conditionsdifferent to those described hereinafter. Hence the figures quoted arenot to be taken as absolute values. The DSC thermogram and TGA for Form1 ZD1839 polymorph is shown in FIG. 2 hereinafter. This polymorph has amelting point in the range of about 194° C. to 198° C. Moreparticularly, the melting point is in the range of about 194.5° C. to196.5° C. Most particularly, the melting point is in the range of about195° C. to 196° C.

DRIFT spectroscopy data were obtained on a Nicolet 20SXC spectrometer,the use of which is described in more detail hereinafter. It will beappreciated that slightly different data may be generated if differentequipment and/or conditions of sample preparation are used. Hence thefigures quoted are not to be taken as absolute values. The DRIFTspectroscopy trace for Form 1 ZD1839 polymorph is shown in FIG. 3hereinafter with distinguishing peaks at about 3400, 1630, 1525, 1245and 840 cm⁻¹.

In addition, there is the potential for Form 1 ZD1839 polymorph to becharacterised and/or distinguished from other physical forms by othertechniques for example using NIR spectroscopy or solid state nuclearmagnetic resonance spectroscopy.

In addition, the crystal structure of Form 1 ZD1839 polymorph wascharacterised by single-crystal X-ray analysis as described in moredetail hereinafter. This polymorph crystallises in the triclinic spacegroup P(−1) with two ZD1839 molecules in the unit-cell and the unit-celldimensions are: a=8.876(1), b=9.692(1), c=12.543(1) Å, α=93.51(1),β=97.36, γ=101.70(1)° and V=1043.6(2) Å³. Other data are shown in TablesA:1 and A:2 hereinafter within Example 5.

The compound of Formula I in the form of the metastable anhydrate ZD1839polymorph when characterised by a DSC thermogram shows an initialexothermic event associated with conversion from the metastable form toForm 1 ZD1839 polymorph which, as disclosed hereinbefore, has anendothermic event corresponding to a melting point in the range of about194° C. to 198° C.

The compound of Formula I in the form of Form 2 ZD1839 MeOH solvate hasthe X-ray powder diffraction pattern shown in FIG. 4 hereinafter havingcharacterising peaks [on the 2 theta (θ) scale] at about 6.5 (largestpeak), 10.0 and 13.2°.

The DSC thermogram and TGA for Form 2 ZD1839 MeOH solvate is shown inFIG. 5 hereinafter. The trace shows an initial endotherm atapproximately 130° C. and a second endotherm at approximately 196° C.The second endotherm corresponds to that from the DSC thermogram fromForm 1 ZD1839 polymorph and indicates that desolvation and a conversionto Form 1 ZD1839 polymorph has occurred on heating. The TGA shows asolvent loss of approximately 3% by weight at approximately 130° C. ThusForm 2 ZD1839 MeOH solvate has a desolvation point in the range of about110° C. to 140° C. More particularly, the desolvation point is in therange of about 125° C. to 138° C.; even more particularly, in the rangeof about 125° C. to 130° C.

The DRIFT spectroscopy trace for Form 2 ZD1839 MeOH solvate is shown inFIG. 6 hereinafter with distinguishing peaks at about 3380, 1650, 1530,1450, 1235, 870 and 570 cm^(−1.)

The compound of Formula I in the form of Form 3 ZD1839 DMSO solvate hasthe X-ray powder diffraction pattern shown in FIG. 7 hereinafter havingcharacterising peaks [on the 2 theta (θ) scale] at about 8.9, 17.8, 22.6(largest peak) and 23.20.

The DSC thermogram and TGA for Form 3 ZD1839 DMSO solvate is shown inFIG. 8 hereinafter. The TGA shows a solvent loss of approximately 14% byweight over a temperature range of approximately 80 to 105° C. The DSCtrace shows an endotherm at approximately 130° C. Thus Form 3 ZD1839DMSO solvate has a desolvation point in the range of about 125° C. to135° C. More particularly, the desolvation point is in the range ofabout 127° C. to 132° C. Most particularly, the desolvation point isabout 130° C.

The DRIFT spectroscopy trace for Form 3 ZD1839 DMSO solvate is shown inFIG. 9 hereinafter with distinguishing peaks at about 1640, 1520, 1450,880 and 560 cm⁻¹.

The Form 5 ZD1839 trihydrate according to the present invention has theX-ray diffraction pattern shown in FIG. 10 hereinafter havingcharacterising peaks [on the 2 theta (θ) scale] at about the positionsshown in Table 1 below: TABLE 1 2 theta Relative intensity 6.1 S 7.1 VS9.3 VS 14.2 VS 18.5 VS 18.8 VS 19.8 VS 22.3 VS 23.3 VS 24.7 VS 25.7 VS

In particular, the first peak (at 6.1° on the 2θ scale) in Table 1 isunique to Form 5 ZD1839 trihydrate and is not present in any other knownform of the compound of Formula I. Further large characterising peaksare also observed at 7.1° and 25.7° on the 2θ scale.

As mentioned hereinbefore, the intensities of the peaks in the XRPDdiffractogram may exhibit some variability, depending upon themeasurement conditions used. Accordingly, in Table 1 and as quotedhereinafter, relative intensities are not stated numerically. Insteadthe following definitions for intensity are used: % Relative Intensity*Definition  25-100 VS (very strong) 10-25 S (strong)  3-10 M (medium)1-3 W (weak)*The relative intensities are derived from X-ray diffraction patternsmeasured with variable slits.

As will be clear some of the more minor peaks present in the X-raydiffraction pattern in FIG. 10 have been omitted from Table 1.

Melting point and weight loss during heating on the Form 5 ZD1839trihydrate were determined using DSC and TGA respectively using MettlerDSC820E and TG851 with TSO891RO robotic systems, the use of which isdescribed in more detail hereinafter in the Examples. It will beappreciated that alternative readings of melting point may be given byother types of equipment or by using conditions different to thosedescribed hereinafter. Hence the figures quoted are not to be taken asabsolute values. The DSC thermogram and TGA for Form 5 ZD1839 trihydrateis shown in FIG. 11 hereinafter.

The DSC trace in FIG. 11 shows a first endotherm with a peak value atapproximately 100° C. (onset at approximately 89° C.) and a secondendotherm is observed with a peak at about 194° C. to 198° C.,particularly at about 196° C. The second endotherm is a meltingendotherm (onset temperature approximately 195° C.). The secondendotherm corresponds with the melting point of Form 1 ZD1839 polymorphand suggests dehydration and a conversion to Form 1 ZD1839 polymorph hasoccurred on heating the Form 5 ZD1839 trihydrate. The TGA thermogram inFIG. 11 shows an event equivalent to that seen in the DSC tracereflecting loss of water of hydration of about 10.8%, which correspondsto the water content of the trihydrate of the compound of Formula I(theoretical water content loss for trihydrate is 10.79%). No otherevents were observable on the DSC trace. Thus Form 5 ZD1839 trihydratehas a dehydration point in the range of about 70° C. to 120° C. Moreparticularly, the dehydration point is in the range of about 80 to 105°C.; even more particularly, in the range of about 88 to 100° C.

In addition, the crystal structure of Form 5 ZD1839 trihydrate may becharacterised by its unit cell dimensions, determined by single-crystalX-ray analysis as described in more detail hereinafter. Form 5 ZDtrihydrate according to the present invention is further characterizedby a monoclinic unit cell with parameters: a=14.41 Å, b=24.89 Å, c=6.81Å, α=90 °, β=92.20, γ=90° and V=2440.4 Å³. The unit cell data wasdetermined as described in the Examples. Other single crystal data areshown in the Tables B1 and B2 within Example 9.

The following particular crystalline forms of the compound of theFormula I are disclosed herein:—

-   -   (i) Form 3 ZD1839 DMSO solvate;    -   (ii) Form 2 ZD1839 MeOH solvate;    -   (iii) Form 1 ZD1839 polymorph; and    -   (iv) Form 5 ZD1839 trihydrate.

Each of these entities possesses the same pharmacological properties asthose disclosed in International Patent Application WO 96/33980 forcompounds such as4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholnopropoxy)quinazoline,in particular anti-proliferative activity such as anti-cancer activity.These solvate, hydrate and polymorph entities are described collectivelyhereinafter as the active substance of the invention.

In order to use the active substance of the invention for the treatmentof mammals including humans, it is normally formulated in accordancewith standard pharmaceutical practice as a pharmaceutical composition.Therefore, according to another aspect of the invention there isprovided a pharmaceutical composition which comprises the activesubstance of the invention and a pharmaceutically-acceptable diluent orcarrier.

For example, the compositions of the invention may be in a form adaptedfor oral administration (for example as tablets, lozenges, hard or softcapsules, aqueous or oily suspensions, emulsions, dispersible powders orgranules, syrups or elixirs), for topical administration (for example ascreams, ointments, gels, or aqueous or oily solutions or suspensions),for insufflation (for example as an aqueous suspension) or forparenteral administration (for example as a sterile aqueous or oilysolution for intravenous, subcutaneous, intraperitoneal or intramusculardosing or as a suppository for rectal dosing).

A preferred method of administration is oral administration. The activesubstance of the invention is conveniently administered orally in theform of tablets. Specific examples of tablet formulations are describedhereinafter.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients that are wellknown in the art. Thus, compositions intended for oral use may contain,for example, one or more colouring, sweetening, flavouring and/orpreservative agents.

Standard excipients include, for example, tablet diluents, dispersants,suspending and binding agents, structure formers, tablet lubricants,cryoprotectants and pH modifiers, such as mannitol, sorbitol, lactose,glucose, sodium chloride, acacia, dextran, sucrose, maltose, gelatin,bovine serum albumin (BSA), glycine, mannose, ribose,polyvinylpyrrolidinone (PVP), cellulose derivatives such asmicrocrystalline cellulose, glutamine, inositol, potassium glutamate,magnesium stearate, sodium lauryl sulphate, talc, erythritol, serine andother amino acids, calcium carbonate, magnesium carbonate and other weakbases, and buffer agents, for example disodium hydrogen phosphate,calcium hydrogen phosphate and potassium citrate.

As mentioned herein, the Form 5 ZD1839 trihydrate is particularly stablein the presence of water. Accordingly Form 5 ZD1839 trihydrate isparticularly suitable for administation as an aqueous suspensionformulation. Conventional aqueous suspension formulations are well knownin the art. A suitable suspension formulation comprises, for example, asuspension of Form 5 ZD1839 trihydrate in water, a nonionic surfactant,a water-soluble soluble salt and optionally a pH buffer. Suitalblenon-ionic surfactants include, for example, Polysorbates such asPolysorbate 20. The water-soluble salt may be sodium chloride, in anamount sufficient to render the suspension isotonic. When a buffer ispresent, it will suitably be chosen to maintain the pH of the suspensionat about 7, for example a pH 7 phosphate buffer.

The amount of the active substance of the invention that is combinedwith one or more excipients to produce a single dosage form willnecessarily vary depending upon the host treatment and the particularroute of administration. For example, a formulation intended for oraladministration to humans will conveniently contain, for example, from 1mg to 1 g of active substance compounded with an appropriate andconvenient amount of excipient which may vary from about 5 to about 98percent by weight of the total composition. Preferably the formulationwill comprise, for example, from 50 mg to 750 mg of active substance.More preferably the formulation will comprise, for example, from 100 mgto 500 mg of active substance, especially about 250′ mg of activesubstance.

In using the active substance of the invention for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.2 to 20 mg per kg body weight isreceived, given if required in divided doses. Preferably a daily dose inthe range, for example, 0.5 to 15 mg per kg body weight is received.More preferably a daily dose in the range, for example, 1 to 10 mg perkg body weight is received.

The active substance of the invention shows an acceptable toxicityprofile.

Further details of the uses of the compound of the Formula I andcombinations containing the compound are disclosed in InternationalPatent Application WO 96/33980. The active substance of the inventionpossesses the same pharmacological properties as those disclosed inInternational Patent Application WO 96/33980 for the compound of theFormula I, in particular anti-proliferative activity such as anti-canceractivity. For example, the active substance of the invention is usefulfor the treatment of many common human cancers such as lung (includingsmall cell lung cancer and non small cell lung cancer), breast,prostate, ovarian, colorectal, gastric, brain (including glioma andpituitary adenoma), head and neck, bladder, pancreas, oesophageal,stomach, renal, skin (including malignant melanoma), gynaecological(including cervical, endometrial, vaginal, vulval and uterine) andthyroid cancer and in the treatment of a range of leukaemias, lymphoidmalignancies and solid tumours such as carcinomas and sarcomas. It isfurther expected that the active substance of the invention will beuseful for the treatment of other diseases involving excessive cellularproliferation such as benign skin hyperplasia, for example psoriasis,and benign prostatic hypertrophy (BPH).

The pharmacological properties of the active substance of the inventionmay be assessed using, for example, one or more of the test proceduresdisclosed in International Patent Application WO 96/33980 or equivalenttest procedures that are well within the compass of the man skilled inthe art. Such test procedures from that patent application areincorporated herein by reference.

According to a further aspect of the present invention there is providedthe active substance of the invention as defined hereinbefore for use ina method of treatment of the human or animal body by therapy.

We have found that the active substance of the invention possessesanti-proliferative properties such as anti-cancer properties which arebelieved to arise from its EGF receptor (erbB1) tyrosine kinaseinhibitory activity. Accordingly the active substance of the inventionis expected to be useful in the treatment of diseases or medicalconditions mediated alone or in part by erbB1 receptor tyrosine kinases,i.e. the active substance of the invention may be used to produce anerbB1 receptor tyrosine kinase inhibitory effect in a warm-bloodedanimal in need of such treatment. Thus the active substance of theinvention provides a method for treating the proliferation of malignantcells characterised by inhibition of erbB1 receptor tyrosine kinases,i.e. the active substance of the invention may be used to produce ananti-proliferative effect mediated alone or in part by the inhibition oferbB1 receptor tyrosine kinase. Accordingly the active substance of theinvention is expected to be useful in the treatment of psoriasis and/orcancer by providing an anti-proliferative effect, particularly in thetreatment of erbB1 receptor tyrosine kinase sensitive cancers such aslung, breast, prostate, ovarian, colorectal, gastric, brain, head andneck, bladder, pancreas, oesophageal, stomach, renal, skin,gynaecological and thyroid cancer.

Thus according to this aspect of the invention there is provided theactive substance of the invention as defined hereinbefore for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

Further, according to this aspect of the invention there is provided theuse of the active substance of the invention as defined hereinbefore inthe manufacture of a medicament for use in the production of ananti-proliferative effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of the activesubstance of the invention as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular proliferative disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. Preferablya daily dose in the range, for example, 0.5 to 15 mg per kg body weightis received. More preferably a daily dose in the range, for example, 1to 10 mg per kg body weight is received. A unit dose in the range, forexample, 1 to 1000 mg, conveniently 100 to 750 mg, more conveniently 200to 600 mg, preferably about 250 mg is envisaged.

The active substance of the invention defined hereinbefore may beapplied as a sole therapy or may involve, in addition to the activesubstance of the invention, conventional surgery and/or radiotherapyand/or chemotherapy. Such chemotherapy may include one or more of thefollowing categories of anti-cancer agents:—

-   (i) anti-invasion agents [for example metalloproteinase inhibitors    such as MMP-2 (matrix-metalloproteinase-2) and MMP-9    (matrix-metalloproteinase-9) inhibitors, for example marimastat, and    inhibitors of urokinase plasminogen activator receptor function];-   (ii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as alkylating agents (for    example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea, or, for example, one of the preferred    antimetabolites disclosed in European Patent Application No. 562734    such as    (2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)    N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid);    antitumour antibiotics (for example anthracyclines like adriamycin,    bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,    mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for    example vinca alkaloids like vincristine, vinblastine, vindesine and    vinorelbine and taxoids like taxol and taxotere); and topoisomerase    inhibitors (for example epipodophyllotoxins like etoposide and    teniposide, amsacrine, topotecan and camptothecin);-   (iii) cytostatic agents such as antioestrogens (for example    tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and    iodoxyfene), antiandrogens (for example bicalutamide, flutamide,    nilutamide and cyproterone acetate), LHRH antagonists or LHRH    agonists (for example goserelin, leuprorelin and buserelin),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example as anastrozole, letrazole, vorazole and exemestane) and    inhibitors of 5α-reductase such as finasteride;-   (iv) other inhibitors of growth factor function, for example growth    factor antibodies, growth factor receptor antibodies such as C225,    antibodies to components of the signal transduction cascade, for    example antibodies to erbB2 such as trastuzumab, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors, for example other    inhibitors of the epidermal growth factor family such as    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033), for example inhibitors of the platelet-derived growth    factor family, for example inhibitors of the protein product of the    bcr-abl gene such as imatinib (STI571), for example inhibitors of    the fibroblast growth factor family and for example inhibitors of    the hepatocyte growth factor family;-   (v) antiangiogenic agents such as those which inhibit vascular    endothelial growth factor such as the compounds disclosed in    International Patent Applications WO 97/22596, WO 97/30035, WO    97/32856, WO 98/13354, WO 00/47212 and WO 01/32651 and those that    work by other mechanisms (for example linomide, inhibitors of    integrin αvβ3 function and angiostatin);-   (vi) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and    rofecoxib;-   (vii) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO    02/08213;-   (viii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (ix) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (x) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agents within their approved dosage ranges.

According to this aspect of the invention there is provided apharmaceutical product comprising the active substance of the inventionas defined hereinbefore and an additional anti-cancer agent as definedhereinbefore for the conjoint treatment of cancer.

Processes for the preparation of the following particular crystallineforms of the compound of the Formula I are disclosed herein, namelyprocesses:—

-   -   (i) for preparing Form 3 ZD1839 DMSO solvate;    -   (ii) for preparing Form 2 ZD1839 MeOH solvate;    -   (iii) for preparing Form 1 ZD1839 polymorph; and    -   (iv) for preparing Form 5 ZD1839 trihydrate.

We have discovered a process for preparing a crystalline form of thecompound of the Formula I substantially in the form of Form 3 ZD1839DMSO solvate, preferably substantially free of any other ZD1839 solvateor any Form 1 ZD1839 polymorph. Such a process provides a further aspectof the present invention and comprises, for example, the steps of:—

-   -   (a) heating a mixture of the compound        4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        in dimethyl sulphoxide or a solvent mixture containing dimethyl        sulphoxide and a co-solvent until dissolution has occurred;    -   (b) reducing the temperature of the solvent system to induce        nucleation;    -   (c) maintaining the mixture at a temperature below that at which        nucleation has commenced; and    -   (d) isolating the crystalline solid so deposited.

The mixture may, for example, be heated to reflux until dissolution hasoccurred. Alternatively, the mixture may, for example, be heated to atemperature less than the reflux temperature of the solvent providedthat dissolution of more or less all of the solid material has occurred.It will be appreciated that small quantities of insoluble material maybe removed by filtration of the warmed mixture.

Suitable solvent mixtures include dimethyl sulphoxide and one or moreco-solvents such as a polar protic solvent such as ethanol andisopropanol and/or a non-protic solvent such as tetrahydrofuran,acetone, ethyl acetate and N,N-dimethylformamide. For example, asuitable solvent is dimethyl sulphoxide. A further suitable solvent is amixture of dimethylsulphoxide and ethyl acetate wherein the ratio byvolume of ethyl acetate to dimethyl sulphoxide lies within the range50:1 to 0.05:1, conveniently in the range 20:1 to 0.5:1, for example 1part of ethyl acetate and 1 part of dimethyl sulphoxide, 6 parts ofethyl acetate and 1 part of dimethyl sulphoxide or 13 parts of ethylacetate and 1 part of dimethyl sulphoxide.

The solution of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein dimethyl sulphoxide or a solvent mixture containing dimethylsulphoxide as one component may be removed from the heat source andallowed to cool to ambient temperature or it may be cooled further, forexample to about 0° C. in a bath of ice and water. Alternatively, thesolution may be cooled at a controlled rate to about 0° C. A suitablecooling rate is, for example, about 10° C. per hour.

It will be appreciated that nucleation may occur either spontaneously oron adding one or more seed crystals.

It has been noted that, on occasions, some Form 1 ZD1839 polymorph maycrystallise from the solution of4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineand that such material is transformed into Form 3 ZD1839 DMSO solvate inthe presence of the DMSO in the solvent mixture. The rate of saidtransformation is temperature dependent, transformation having beennoted at ambient temperature and more rapid transformation having beennoted at higher temperatures, for example in the range of about 30 to50° C., conveniently at about 40° C. However, it has also been notedthat at temperatures of above about 50° C. Form 3 ZD1839 DMSO solvate istransformed back to Form 1 ZD1839 polymorph. Accordingly, in an improvedversion of the above-mentioned process for preparing a crystalline formof the compound of the Formula I substantially in the form of Form 3ZD1839 DMSO solvate, once the mixture has been maintained at atemperature below that at which nucleation has commenced, a step isadded of reheating the mixture to a temperature in the range of about30° C. to 50° C., conveniently to about 40° C., for example for a periodof about 1 hour, followed by reducing the temperature of the mixture toabout 0° C. to complete the crystallisation.

The crystalline solid may be isolated by any conventional method, forexample by filtration or centrifugation.

It will be appreciated by the man skilled in the art that the proceduresdescribed above may be varied using routine skill and knowledge. Forexample, provided that a crystalline form of the compound of the FormulaI substantially in the form of Form 3 ZD11839 DMSO solvate is obtained,any of the quantity of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinethat is treated, the volume of the DMSO solvent, the nature and volumeof any co-solvent, the ratio of the component solvents if a solventmixture is employed and the temperatures of the dissolution and coolingphases may be varied.

It will also be appreciated that, when nucleation is induced during anyof the process procedures described herein by the addition of one ormore seed crystals, a quantity of seed crystals having a weight in therange of about 1 to 500 mg may be employed. Preferably a quantity ofseed crystals having a weight in the range of about 1 to 100 mg may beemployed.

In addition Form 3 ZD1839 DMSO solvate may readily be converted into thecompound of Formula I, particularly into Form 1 ZD1839 polymorph.Overall, the inclusion of the steps of DMSO solvate preparation,purification thereof and conversion into Form 1 ZD1839 polymorph isbeneficial in terms of the yield and purity of the Form 1 ZD1839polymorph so obtained. Such a process for the preparation of thecompound of Formula I substantially in the form of Form 1 ZD1839polymorph provides a further aspect of the present invention andcomprises, for example, the steps of:—

-   -   (a) washing Form 3 ZD1839 DMSO solvate with a solvent or solvent        mixture substantially to remove dimethyl sulphoxide; and    -   (b) isolating the Form 1 ZD1839 polymorph so formed.

Suitable solvents include, for example, a polar protic solvent such asethanol or isopropanol or a non-protic solvent such as tetrahydrofuran,acetone, ethyl acetate or N,N-dimethylformamide. Mixtures of suchsolvents may also be employed. Ethyl acetate is a preferred solvent forthis washing procedure. Conveniently the washing solvent may be warmed,for example to a temperature of about 30° C. to 50° C.

It is to be understood that the ‘washing’ step requires a suitableperiod of time. For example, if the Form 3 ZD1839 DMSO solvate is heldon a filter apparatus and the washing solvent is passed through thatsolid too quickly the conversion to Form 1 ZD1839 polymorph will beincomplete. A suitable contact time between the solid and washingsolvent is in the range of about 5 minutes to 1 or more hours. Moreconveniently, the contact time is in the range of about 30 minutes toabout 2 hours, for example about 1 hour. Conveniently, a slurry of thesolid and the washing solvent is prepared. Conveniently, the slurry isstirred to improve contact between the washing solvent and the crystalsof solid. As stated above, conveniently the washing solvent may bewarmed. It will be appreciated that, during the washing step, portionsof the Form 3 ZD1839 DMSO solvate are dissolved in the washing solventand from the solution so formed Form 1 ZD1839 polymorph crystallises.However, it is not necessary for all of the Form 3 ZD1839 DMSO solvateto be in solution prior to the commencement of the crystallisation ofthe Form 1 ZD1839 polymorph. Hence the washing step described hereinconcerns a portionwise dissolution and conversion of form of the Form 3ZD1839 DMSO solvate.

The crystalline solid may be isolated by any conventional method, forexample by filtration or centrifugation.

Conveniently, the compound of Formula I substantially in the form ofForm 1 ZD1839 polymorph that is obtained from the washing step may bepurified further by recrystallisation. For example, the washed solid maybe warmed in a suitable solvent as defined hereinbefore untildissolution has occurred, the temperature of the solution may be reducedto induce nucleation either spontaneously or on adding one or more seedcrystals, the temperature of the solution may be maintained below thatat which nucleation has commenced and the crystalline solid so depositedmay be isolated.

We have also discovered a process for preparing a crystalline form ofthe compound of the Formula I substantially in the form of Form 2 ZD1839MeOH solvate, preferably substantially free of any other ZD1839 solvateor any Form 1 ZD1839 polymorph. Such a process provides a further aspectof the present invention and comprises, for example, the steps of:—

-   -   (a) heating a mixture of the compound        4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        in methanol or a solvent mixture containing methanol and a        co-solvent until dissolution has occurred;    -   (b) reducing the temperature of the solvent system to induce        nucleation;    -   (c) maintaining the mixture at a temperature below that at which        nucleation has commenced; and    -   (d) isolating the crystalline solid so deposited.

The mixture may, for example, be heated to reflux until dissolution hasoccurred. The mixture may then be removed from the heat source andallowed to cool to ambient temperature or it may be cooled further, forexample to about 0° C. in a bath of ice and water. Alternatively, thesolution may be cooled at a controlled rate to about 0° C. A suitablecooling rate is, for example, about 10° C. per hour.

It will be appreciated that nucleation may occur either spontaneously oron adding one or more seed crystals.

Suitable solvent mixtures include methanol and one or more co-solventssuch as weakly polar solvents, for example aromatic hydrocarbons such astoluene, halogeno-(1-6C)alkanes such as 1,2-dichloroethane and aliphaticdi-(1-6C)alkyl ethers or (4-7C)cyclic ethers such as tetrahydrofuran,other polar protic solvent such as ethanol and isopropanol, polarnon-protic solvents such as aliphatic esters such as ethyl acetate,aliphatic (3-6C)ketones such as acetone and aliphatic amides such asN,N-dimethylformamide. For example, a suitable solvent is methanol. Afurther suitable solvent is a mixture of methanol and a co-solventselected from toluene and ethyl acetate where, for example, the ratio byvolume of co-solvent to methanol lies within the range 50:1 to 0.05:1,conveniently in the range 20:1 to 0.5:1.

The solution of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein methanol or a solvent mixture containing methanol as one componentmay be removed from the heat source and cooled as described hereinbeforefor the preparation of Form 3 ZD1839 DMSO solvate.

The crystalline solid may be isolated by any conventional method, forexample by filtration or centrifugation.

It will be appreciated by the man skilled in the art that the proceduresdescribed above may be varied using routine skill and knowledge. Forexample, provided that a crystalline form of the compound of the FormulaI substantially in the form of Form 2 ZD1839 MeOH solvate is obtained,any of the quantity of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinethat is treated, the volume of the methanol solvent, the nature andvolume of any co-solvent, the ratio of the component solvents if asolvent mixture is employed and the temperatures of the dissolution andcooling phases may be varied.

In addition Form 2 ZD1839 MeOH solvate may be converted into thecompound of Formula I, particularly into Form 1 ZD1839 polymorph. Such aprocess for the preparation of the compound of Formula I in the form ofForm 1 ZD1839 polymorph provides a further aspect of the presentinvention and comprises, for example, the steps of

-   -   (a) washing Form 2 ZD1839 MeOH solvate with a solvent or solvent        mixture substantially to remove methanol; and    -   (b) isolating the Form 1 ZD1839 polymorph so formed.

Suitable solvents include, for example, a polar protic solvent such asethanol or isopropanol or a non-protic solvent such as tetrahydrofuran,acetone, ethyl acetate or N,N-dimethylformamide. Mixtures of suchsolvents may also be employed. Ethyl acetate is a preferred solvent forthis washing procedure. Conveniently the washing solvent may be warmed,for example to a temperature of about 30° C. to 50° C.

It will be appreciated that the washing step as described hereinconcerns a portionwise dissolution and conversion of form of the Form 2ZD1839 MeOH solvate.

The crystalline solid may be isolated by any conventional method, forexample by filtration or centrifugation.

Conveniently, the compound of Formula I substantially in the form ofForm 1 ZD1839 polymorph that is obtained from the washing step may bepurified further by recrystallisation. For example, the washed solid maybe warmed in a suitable solvent as defined hereinbefore untildissolution has occurred, the temperature of the solution may be reducedto induce nucleation either spontaneously or on adding one or more seedcrystals, the temperature of the solution may be maintained below thatat which nucleation has commenced and the crystalline solid so depositedmay be isolated.

In addition, Form 2 ZD1839 MeOH solvate may be converted into thecompound of Formula I in the form of Form 1 ZD1839 polymorph by warmingthe compound, for example by heating the compound to a temperature ofabout 125° C. to 150° C., more particularly to a temperature of morethan about 135° C.

A process for preparing a crystalline form of the compound of theFormula I substantially in the form of Form 1 ZD1839 polymorph has alsobeen obtained. Preferably, the crystalline form of the compound of theFormula I substantially in the form of Form 1 ZD1839 polymorph isobtained substantially free of any other polymorphic form of ZD1839 orof any ZD1839 solvate. Such a process comprises, for example, the stepsof:—

-   -   (a) dissolving the compound        4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        in a solvent system in which solvate formation is repressed;    -   (b) reducing the temperature of the solvent system to induce        nucleation;    -   (c) maintaining the mixture at a temperature below that at which        nucleation has commenced; and    -   (d) isolating the crystalline solid so deposited.

Suitable solvent systems in which solvate formation is repressed includeweakly polar solvents, for example aromatic hydrocarbons such astoluene, halogeno-(1-6C)alkanes such as 1,2-dichloroethane and aliphaticdi-(1-6C)alkyl ethers or (4-7C) cyclic ethers such as tetrahydrofuran,more polar protic solvents, for example (2-6C) alcohols such as ethanoland isopropanol, and polar non-protic solvents such as aliphatic esterssuch as ethyl acetate, aliphatic (3-6C) ketones such as acetone andaliphatic amides such as N,N-dimethylformamide. Mixtures of suchsolvents may also be employed such as a mixture of toluene andisopropanol where, for example, the ratio by volume of toluene toisopropanol conveniently lies within the range 5:1 to 0.2:1, moreconveniently in the range 2:1 to 0.5:1.

The solution of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay be removed from the heat source and allowed to cool to ambienttemperature or it may be cooled further, for example to about 0° C. in abath of ice and water. Alternatively, the solution may be cooled at acontrolled rate to about 0° C. A suitable cooling rate is, for example,about 10° C. per hour. It will be appreciated that the nucleation mayoccur either spontaneously or on adding one or more seed crystals. Thecrystalline solid so obtained may be isolated by any conventionalmethod, for example by filtration or centrifugation.

Conveniently, the solution of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay be removed from the heat source and allowed to cool to about 30° C.The mixture may be reheated to about 50° C. The mixture may then beallowed to cool to ambient temperature or it may be cooled further, forexample to about 0° C. in a bath of ice and water. Alternatively, thesolution may be cooled from about 50° C. at a controlled rate to about0° C. A suitable cooling rate is, for example, about 10° C. per hour.The crystalline solid so obtained may be isolated by any conventionalmethod, for example by filtration or centrifugation.

It will be appreciated by the man skilled in the art that the proceduresdescribed above may be varied using routine skill and knowledge. Forexample, provided that Form 1 ZD1839 polymorph is obtained substantiallyfree of any other ZD1839 polymorph or any ZD1839 solvate, any of thequantity of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinethat is treated, the nature and volume of the solvent and anyco-solvent, the ratio of the component solvents if a solvent mixture isemployed and the temperatures of the dissolution and cooling phases maybe varied. For example, a solution of the compound of the Formula I in asuitable solvent, for example a (2-6C) alcohol such as ethanol may beallowed to become concentrated by the evaporation of some of thesolvent. Thereby a supersaturated solution is obtained from which Form 1ZD1839 polymorph crystallises.

In a further aspect of the present invention there is provided a processfor preparing a compound of the Formula I substantially in the form ofForm 5 ZD1839 trihydrate (preferably substantially free of any otherZD1839 solvate or any other form of ZD1839) which comprises:—

-   -   (a) contacting        4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        with water for a sufficient time to convert the        (3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        to the Form 5 trihydrate; and    -   (b) isolating the Form 5 ZD1839 trihydrate.

The4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineused as the starting material in step (a) of the process may be any formof the compound of Formula I, for example prepared as described in theprior art or prepared as one of the forms described herein, particularlyForm 1 ZD1839 polymorph.

Conveniently, conversion to the Form 5 ZD1839 trihydrate is effected bypreparing a slurry of the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material in water, optionally in the presence of one or moresuitable organic solvent(s). Generally a molar excess of water is usedto ensure substantially complete conversion of the4-(3′-chloro-4′-fluoroanilino)₇-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material to the Form 5 ZD1839 trihydrate (i.e. the molar ratioof water:4-(3′-chloro-4′-fluoroanilino)₇-methoxy-6-(3-morpholinopropoxy)quinazolineis at least 3:1). The upper limit of water concentration is notcritical, however, generally a large molar excess of water is used. Forexample the molar ratio of water to4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineis suitably from about 3:1 to 1000:1 or more, particularly from about3:1 to about 400:1.

In a particular embodiment, a slurry of the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material (such as Form 1 ZD1839 polymorph) is prepared in amixture of water and an organic solvent, and optionally one or moreco-solvents. We have found that the use of an organic solventsignificantly reduces the time required to convert the starting materialto the Form 5 ZD1839 trihydrate. Suitable organic solvents arewater-miscible polar organic solvents, such as polar protic solvents,for example (1-4C) alcohols, particularly ethanol and isopropanol, polarnon-protic solvents such as aliphatic esters, for example a (1-4C) allyl(2-3C)alkanoate ester, particularly ethyl acetate, aliphatic (3-6C)ketones such as acetone or aliphatic amides such asNIN-dimethylformamide. Particular solvents include, for exampleisopropanol or ethyl acetate, or a mixture thereof.

The amount of organic solvent used is generally insufficient tocompletely dissolve the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material such that a slurry is retained throughout the process.We have found that by retaining the compound of the Formula I in aslurry during the process enables the ZD1839 trihydrate to be formedwithout the need to induce crystallisation by, for example, cooling themixture or evaporating solvent. Accordingly the slurry process may beoperated at a substantially constant temperature.

Without wishing to be bound by theory, it is thought that the conversionprocess proceeds via a mechanism of localised dissolution of the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material and subsequent recrystallisation to the Form 5 ZD1839trihydrate. Hence the slurry conversion process described herein isthought to be a portionwise dissolution and conversion of the startingmaterial to the Form 5 ZD1839 trihydrate.

The specific amount of organic solvent used will be dependent upon theorganic solvent selected and the conditions under which the slurry iscontacted with the water. In the case of solvents such as isopropanol orethyl acetate a range of 0.1 to 20 ml/g, such as 2 to 10 ml/g andparticularly approximately 5 ml/g is suitable, wherein “ml/g” refers tothe volume of organic solvent per g of the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline.

When the organic solvent is one with which the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay form solvates, for example methanol or isopropanol, the slurryprocess described above should be operated under conditions that repressthe formation of solvates with the organic solvent. In the case ofisopropanol we have found that a large excess of isopropanol can resultin the formation of a metastable isopropanolate dihydrate. The formationof such undesirable solvates is substantially repressed in the slurryprocess described above by selecting a volume ratio of isopropanol towater of less than 10:1, particularly less than 8:1 and especially lessthan 5:1. Particularly we have found that a volume ratio of isopropanolto water of from about 1:5 to 5:1, particularly from 1:5 to 2:1 and moreparticularly about 1:11 to 1:2, favours formation of the Form 5 ZD1839trihydrate over the metastable isopropanolate.

A single organic solvent may be used or two or more organic solvents,for example a mixture of ethyl acetate and isopropanol (suitably in avolume ratio of approximately 1:1), may be used, together with thewater.

Optionally a co-solvent may be used. Suitable co-solvents include, forexample, weakly polar organic solvents such as aromatic hydrocarbons(for example toluene), halogeno-(1-6C)alkanes (for example1,2-dichloroethane) and aliphatic di-(1-6C)alkyl ethers or (4-7C)cyclicethers (for example tetrahydrofuran). A particular co-solvent istoluene. A suitable ratio by volume of co-solvent (such as toluene) toorganic solvent (such as isopropanol) lies within the range 50:1 to0.05:1, conveniently in the range 10:1 to 0.5:1, and particularly fromabout 3:1 to 1:1.

As will be appreciated, the slurry of the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,water and optional organic solvent and co-solvent may be prepared in anyorder. For example, the starting material may be prepared as a slurry inthe organic solvent (and optional co-solvent) followed by addition ofthe water. Alternatively the starting material may be prepared as aslurry in water followed by addition of the solvent (and co-solvent, ifpresent), or the starting material may be prepared as a slurry directlyin the water and organic solvent.

Optionally, one or more seeding crystal(s) of the Form 5 ZD1839trihydrate may be added to the slurry to further enhance the rate ofconversion to the Form 5 ZD1839 trihydrate and/or yield of Form 5 ZD1839trihydrate. The seeding crystals may be added after or, preferably,prior to contact of the Form 1 ZD1839 polymorph with the water. Suitablythe slurry is agitated during the process, for example by stirring.

The process is suitably carried out at about ambient temperature, forexample from approximately 15 to 30° C., particularly approximately 20to 25° C.

The time required for conversion to the Form 5 trihydrate is dependentupon the particular reaction conditions used, such as temperature,presence of an organic solvent and whether seeding crystals are used.Generally, a reaction time of, for example, from 5 minutes to 48 hoursis suitable.

The crystalline solid Form 5 ZD1839 trihydrate may be isolated by anyconventional method, for example by filtration or centrifugation.

It will be appreciated by the man skilled in the art that the proceduresdescribed above may be varied using routine skill and knowledge. Forexample, provided that a crystalline form of the compound of the FormulaI substantially in the form of Form 5 ZD1839 trihydrate is obtained, anyof the quantity of the compound4-(3′-chloro-4′-fluoroanilino)₇-methoxy-6-(3-morpholinopropoxy)quinazolinethat is treated, the volume of water, the nature and volume of anysolvent or co-solvent, the ratio of the component solvents if a solventmixture is employed and the temperature of the process may be varied.

In a further aspect of the present invention there is provided a processfor crystallising (or recrystallising) a compound of the Formula Isubstantially in the form of Form 5 ZD1839 trihydrate (preferablysubstantially free of any other ZD1839 solvate or any other form ofZD1839) which comprises the steps:—

-   -   (a) dissolving the compound        4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline        in a solvent system comprising water and an organic solvent;    -   (b) reducing the temperature of the solvent system to induce        nucleation;    -   (c) maintaining the mixture at a temperature below that at which        nucleation has commenced; and    -   (d) isolating the crystalline Form 5 ZD1839 trihydrate.

Suitable organic solvents in the solvent system include organic solventswhich are: (i) water-soluble at the temperature at which the startingmaterial in step (a) of the process is dissolved; and (ii) organicsolvents which, when used in the solvent system, repress the formationof solvates other than the trihydrate. Suitable organic solventsinclude, for example, weakly polar organic solvents such as aliphaticdi-(1-6C)alkyl ethers or (4-7C)cyclic ethers such as tetrahydrofuran,more polar protic solvents, for example (2-6C) alcohols such as ethanoland isopropanol, polar non-protic solvents such as (1-4C) allyl(2-3C)alkanoate esters such as ethyl acetate, aliphatic (3-6C) ketonessuch as acetone, aliphatic amides such as N,N-dimethylformamide orN-methylpyrrolidin-2-one and nitriles such as acetonitrile. A particularorganic solvent is, for example isopropanol. A single organic solvent ora mixture of one or more of the above solvents may be used.

Generally a molar excess of water is used in the solvent system (i.e.the molar ratio of water:4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineis at least 3:1). The upper limit of water concentration is notcritical, however, generally a large molar excess of water is used. Forexample the molar ratio of water to4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineis suitably from about 3:1 to 1000:1 or more, particularly from about3:1 to about 400:1.

Optionally, a co-solvent may be used in the solvent system. Suitableco-solvents include, for example, aromatic hydrocarbons such as tolueneand aliphatic halogenated hydrocarbons such as halogeno-(1-6C)alkanes,for example 1,2-dichloroethane. A particular organic solvent/co-solventwhich may be used in the solvent system is, for example, a mixture oftoluene and isopropanol where, for example, the ratio by volume oftoluene to isopropanol conveniently lies within the range 5:1 to 0.2:1,more conveniently in the range 2:1 to 0.5:1.

The compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay be dissolved in step (a) of the process by heating the compound inthe solvent system until substantially all of the compound hasdissolved. Conveniently the compound in the solvent system in step (a)of the process is heated at the reflux temperature of the solvent systemfor sufficient time to completely dissolve the compound. The solution ofthe compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay then be removed from the heat source and allowed to cool to ambienttemperature or it may be cooled further, for example to about 0° C. in abath of ice and water. Alternatively, the solution may be cooled at acontrolled rate to about 0° C. A suitable cooling rate is, for example,about 10° C. per hour. It will be appreciated that the nucleation mayoccur either spontaneously or on adding one or more seed crystals. Thecrystalline Form 5 ZD1839 trihydrate so obtained may be isolated by anyconventional method for example by filtration or centrifugation.

As mentioned herein, under certain conditions it is possible to form ametastable isopropanolate dihydrate form of the compound of Formula I.We have found that when the compound of Formula I is crystallised orrecrystallised from a solvent system containing isopropanol, thecompound of Formula I may be prepared in high purity substantially asthe Form 5 ZD1839 trihydrate and substantially in the absence ofisopropanolate solvates by selecting suitable volume ratios of water toisopropanol and/or a suitable co-solvent and/or a suitable cooling rateand/or appropriate seeding to induce nucleation and crystallisation.

In one embodiment of this process, when the solvent system compriseswater and isopropanol and optionally toluene co-solvent, a volume ratioof water to isopropanol of from about 1.5:1 to 1:12 (particularly fromabout 1.3:1 to 1:10, more particularly about 1.2:1 to 1:2 and still moreparticularly at about 1:1), in conjunction with a slow cooling to inducenucleation of the Form 5 ZD1839 trihydrate gives the Form 5 ZD1839trihydrate substantially in the absence of other forms of the compoundof Formula I, particularly the absence of isopropanolates. A suitableslow cooling rate in this embodiment is, for example, cooling from thereflux temperature of the solvent system to about ambient temperature ata cooling rate of about 10° C. per hour. Alternatively in thisembodiment, the solution of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemay be removed from the heat source and allowed to cool to about 30° C.to encourage nucleation of the Form 5 ZD1839 trihydrate. The mixture maybe reheated to about 50° C. and then be allowed to cool to ambienttemperature or it may be cooled further, for example to about 0° C. in abath of ice and water. Alternatively, the solution may be cooled fromabout 50° C. at a controlled rate to about 0° C. A suitable cooling rateis, for example, about 10° C. per hour. Nucleation of the Form 5 ZD1839trihydrate may also be induced by addition of one or more seed crystals.

The crystalline Form 5 ZD1839 trihydrate: so obtained may be isolated byany conventional method, for example by filtration or centrifugation.

When one or more seed crystals are used to initiate nucleation in thecrystallisation/recrystallisation processes described above, the seedcrystals are preferably crystals of the Form 5 ZD1839 trihydrate. Theseed crystal(s) may be prepared using any suitable method for thepreparation of Form 5 ZD1839 trihydrate, for example by slurrying asample of the Form 1 ZD1839 polymorph in water as hereinbeforedescribed.

It will be appreciated by the man skilled in the art that the proceduresdescribed above may be varied using routine skill and knowledge. Forexample, provided that Form 5 ZD1839 trihydrate is obtainedsubstantially free of any other ZD1839 polymorph or any ZD1839 solvate,any of the quantity of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinethat is treated, the nature and volume of the solvent and anyco-solvent, the ratio of the component solvents if a solvent mixture isemployed, the volume of water used and the ratio of water to solvent andthe temperatures of the dissolution and cooling phases may be varied.For example, nucleation of a solution of the compound of the Formula Iin a suitable solvent, for example a (2-6C) alcohol such as ethanol instep (b) of the process may be induced by, for example, the evaporationof some of the ethanol solvent, alternatively, nucleation could beinduced by the addition of a suitable antisolvent for the compound ofFormula I, thereby creating supersaturation and nucleation of thesolution from which Form 5 ZD1839 trihydrate crystallises.

The crystallisation process for preparing the Form 5 ZD1839 trihydrateenables the trihydrate to be prepared in high purity, furthermorerecrystallisation of the Form 5 ZD1839 trihydrate so obtained may becarried out using the process described above. Recrystallisation offersthe possibility for further purifying the material.

We have also found that the Form 5 ZD1839 trihydrate can be readilyconverted to the Form 1 ZD1839 polymorph. Accordingly, crystallisationof the Form 5 ZD1839 trihydrate and subsequent conversion to the Form 1ZD1839 polymorph provides a means for preparing the Form 1 ZD1839polymorph in high purity. Such a process for the preparation of thecompound of Formula I substantially in the form of Form 1 ZD1839polymorph (preferably substantially free of any other ZD1839 solvate orany other form of ZD1839) provides a further aspect of the presentinvention and comprises, for example:−

Conversion Process 1

-   -   (a) washing compound of Formula I substantially in the form of        Form 5 ZD1839 trihydrate with a solvent or solvent mixture        substantially to remove water; and    -   (b) isolating the Form 1 ZD1839 polymorph so formed; or        Conversion Process 2    -   by heating compound of Formula I substantially in the form of        Form 5 ZD1839 trihydrate for a sufficient time and at sufficient        temperature to drive off water and effect transformation to Form        1 ZD1839 polymorph.

In conversion process 1, a suitable solvent includes, for example,water-miscible organic solvents in which the compound of Formula I issparingly soluble at the washing temperature. Examples of suitablesolvents include, weakly polar organic solvents such as aliphaticdi-(1-6C)alkyl ethers or (4-7C)cyclic ethers such as tetrahydrofuran,more polar protic solvents, for example (2-6C) alcohols such as ethanoland isopropanol, polar non-protic solvents such as (1-4C)alkyl(2-3C)alkanoate esters such as ethyl acetate and nitriles such asacetonitrile. Mixtures of such solvents may also be employed. Aparticular solvent is isopropanol and/or ethyl acetate.

As described above in relation to the conversion of the Form 3 ZD1835DMSO solvate, it is to be understood that the ‘washing’ step requires asuitable period of time to effect conversion to the Form 1 ZD1839polymorph. A suitable contact time between the solid and washing solventis in the range of about 5 minutes to 1 or more hours. Moreconveniently, the contact time is in the range of about 30 minutes toabout 2 hours, for example about 1 hour. Conveniently, a slurry of thesolid and the washing solvent is prepared. Conveniently, the slurry isstirred to improve contact between the washing solvent and the crystalsof solid. The washing solvent may be warmed, for example to atemperature of about 30 to 50° C., however, generally washing at aboutambient temperature is sufficient to effect conversion to the Form 1ZD1839 polymorph.

In a particular embodiment of conversion process (a), the Form 5 ZD1839trihydrate is washed with isopropanol, suitably by stirring a slurry ofthe Form 5 ZD1839 trihydrate in isopropanol for approximately 5 minutesto 1 hour or more, particularly about 30 minutes. Conveniently, theisopropanol wash is carried out at about ambient temperature. Theresulting solid is then isolated, for example as hereinbefore described(such as by filtration) and the isolated solid is washed for a secondtime with an additional organic solvent. Suitably the additional organicsolvent is one that is more volatile than the isopropanol, for exampleethyl acetate. The second wash is, for example, carried out by stirringthe solid as a slurry in the additional organic solvent. Suitably thesecond wash is carried out at approximately ambient temperature and forsufficient time to substantially remove any remaining water from thesolid material, for example from 5 minutes to 1 hour or more,particularly about 30 minutes. The resulting Form 1 ZD1839 polymorph maythen be isolated using conventional techniques as hereinbeforedescribed.

Optionally, the material isolated following the solvent washing step(s)in conversion process 1 is dried to ensure complete removal of water andconversion to the desired Form 1 ZD1839 polymorph. A suitable dryingtemperature is, for example, from 45 to 150° C., particularly from 60 to80° C. As will be recognised, the drying time will be dependent upon,amongst other things, the amount of material to be dried, and theparticular drying method used. Generally a drying time of 30 minutes to100 hours, for example 1 to 30 hours is sufficient. Conveniently thedrying is performed under an inert atmosphere, for example by passing astream of warm inert gas such as nitrogen over or through the materialor by drying under vacuum.

Conversion process 2 is suitably carried out by heating the Form 5ZD1839 trihydrate at a temperature of from 50 to 150° C., particularlyfrom 80 to 140° C., more particularly from 120 to 130° C. The heatingtime required is dependant on, amongst other things, the size of thesample and the heating method employed. Generally a heating time of from5 minutes to 100 hours, suitably 1 to 30 hours, is sufficient to convertthe Form 5 ZD1839 trihydrate to Form 1 ZD1839 polymorph. The Form 5ZD1839 trihydrate may be heated using conventional techniques, forexample in a suitable oven or vacuum oven or in a conventional dryingsystem such as a fluid bed dryer.

It is thought that the heating of Form 5 ZD1839 trihydrate may result inthe transient formation of one or more metastable forms of the compoundof the Formula I, including a metastable anhydrous ZD1839 polymorph. Anysuch metastable forms are less stable that the Form 1 ZD1839 polymorphand continued heating results in transformation of the transientmetastable forms to the more stable Form 1 ZD1839 polymorph.Accordingly, the heating step in conversion process 2 should becontinued for sufficient and at sufficient temperature time to ensuresubstantially complete conversion to the desired Form 1 ZD1839polymorph. By substantially complete conversion is meant that at least80% of the compound of the Formula I is in the form of Form 1 ZD1839polymorph and less than 20% of the compound of the Formula I is in theform of any other ZD1839 solvate or any other ZD1839 polymorph.Particularly at least 90% and, in particular, at least 95% of thecompound of the Formula I is in the form of Form 1 ZD1839 polymorph. Thedegree of conversion to the required Form 1 ZD1839 polymorph may beassessed using routine techniques, for example XRPD as described hereinand the heating temperature and/or time adjusted accordingly.

The invention is illustrated hereinafter by means of the followingExamples, data and Figures in which:—

-   (i) X-ray diffraction patterns were obtained using a Siemens D5000    machine in θ-θ configuration over the scan range 2° 2θ to 40° 2θ    with 4 seconds exposure per 0.02° 2θ increment. The X-rays were    generated by a copper long-fine focus tube operated at 40 kV and 40    mA. The wavelength of the X-rays was 1.5406 Å. The examinations were    carried out in Bragg-Brentano configuration whereby the X-ray beam    was passed through an Automatic Variable Divergence Slit at V20. The    sample was prepared by gently breaking up crystal aggregates using    an agate pestle and mortar. The sample was filled into a standard    holder (having a flat lip) and compressed flush to the lip with a    glass microscope slide. The sample was spun at 30 revolutions per    minute (rpm) to improve counting statistics. The reflections are    quoted as their centroid values (calculated by a computer package    such as DIFFRAC/AT). It should be realised that analysis of samples    with grains above 30 microns in size and non-unitary aspect ratios    may affect the relative intensity of peaks. The skilled person will    also realise that the position of reflections is affected by the    precise height at which the sample sits in the diffractometer and    the zero calibration of the diffractometer. The surface planarity of    the sample may also have a small effect. Hence the diffraction    pattern data presented are not to be taken as absolute values.-   (ii) Melting points and TGA in Examples 1 to 5 were determined using    Perkin Elmer Pyris 1 DSC/TGA equipment. The pan type was aluminium    (50 μl size) with a pierced lid. The sample weight was approximately    1 to 4 mg. Melting point and weight loss during heating on the Form    5 ZD1839 trihydrate in Examples 6 to 8 were determined using DSC and    TGA respectively using Mettler DSC820E and TG851 with TSO891RO    robotic systems. The pan type was aluminium (40 μl size) with a    pierced lid. The procedures were carried out under a flow of    nitrogen gas (100 ml/min) and the temperature range studied was    40° C. to 300° C. at a constant rate of temperature increase of    10° C. per minute. The skilled person will realise that the precise    value of the melting point will be influenced by the purity of the    compound, the sample weight, the heating rate and the particle size.    It will therefore be appreciated that alternative readings of    melting point may be given by other types of equipment or by using    conditions different to those described. For the TGA, each sample    (approximately 2 mg) was heated in an open ceramic crucible from    15° C. to 300° C. at a rate of 10° C. per minute.-   (iii) DRIFT spectroscopy was recorded on a Nicolet 20SXC    spectrometer using a 2% w/w dispersion of the sample in powdered    potassium bromide over the frequency range 4000 to 400 cm⁻¹.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern for Form 1 ZD1839polymorph with the 2θ values plotted on the horizontal axis and therelative line intensity (Count) plotted on the vertical axis.

FIG. 2 shows the DSC thermogram and TGA trace for Form 1 ZD1839polymorph with temperature (° C.) plotted on the horizontal axis andendothermic heat flow (milliWatts (mW)) and sample weight (percentage ofinitial weight) plotted on the two vertical axes.

FIG. 3 shows the DRIFT spectrum for Form 1 ZD1839 polymorph with thefrequency range 4000 to 400 cm⁻¹ plotted on the horizontal axis andabsorbance plotted on the vertical axis.

FIG. 4 shows the X-ray powder diffraction pattern for Form 2 ZD1839 MeOHsolvate with the 2θ values plotted on the horizontal axis against anexpanded scale of relative line intensity values (Count) plotted on thevertical axis.

FIG. 5 shows the DSC thermogram and TGA trace for Form 2 ZD1839 MeOHsolvate with temperature (° C.) plotted on the horizontal axis andendothermic heat flow (mW) and sample weight (percentage of initialweight) plotted on the two vertical axes.

FIG. 6 shows the DRIFT spectrum for Form 2 ZD1839 MeOH solvate.

FIG. 7 shows the X-ray powder diffraction pattern for Form 3 ZD1839 DMSOsolvate with the 2θ values plotted on the horizontal axis againstrelative line intensity values (Count) plotted on the vertical axis.

FIG. 8 shows the DSC thermogram and TGA trace for Form 3 ZD1839 DMSOsolvate with temperature (° C.) plotted on the horizontal axis andendothermic heat flow (mW) and sample weight (percentage of initialweight) plotted on the two vertical axes.

FIG. 9 shows the DRIFT spectrum for Form 3 ZD1839 DMSO solvate.

FIG. 10 shows the X-ray powder diffraction pattern for Form 5 ZD1839trihydrate with the 2θ values plotted on the horizontal axis and therelative line intensity (Count) plotted on the vertical axis.

FIG. 11 shows the DSC thermogram (solid line) and TGA trace (dottedline) for Form 5 ZD1839 trihydrate with temperature (° C.) plotted onthe horizontal axis and endothermic heat flow (milliwatts (mW)) andsample weight (mg) shown on the two scale bars.

EXAMPLE 1 Form 3 ZD1839 DMSO Solvate4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinemono-solvate with dimethyl sulphoxide

With warming to about 75° C.,4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline(204 kg) was dissolved in a mixture of ethyl acetate (1021 litres) anddimethyl sulphoxide (181 litres) containing diatomaceous earth filteraid (5 kg). The resultant mixture was filtered and ethyl acetate (78litres) was used to wash the filter aid solid. The filtrate and washingswere combined and cooled initially to about 10° C. The mixture was thenheated to about 40° C. for 1 hour. The warm mixture was cooled to 0° C.at a rate of about 10° C. per hour. The resultant solid was collected byfiltration. There was thus obtained Form 3 ZD1839 DMSO solvate as shownby XRPD and DSC analysis.

The4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineused as a starting material is disclosed in International PatentApplication WO 96/33980 within Examples 1 and 10. The material may alsobe obtained as described in Example 4 hereinafter.

EXAMPLE 2 Form 2 ZD1839 MeOH Solvate4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinehemi-methanolate

A mixture of4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline(25 g) and methanol (250 ml) was stirred and heated to reflux for 30minutes to ensure that the solid was fully in solution. The solution wascooled down at a rate of about 10° C. per hour from the refluxtemperature to a temperature of 0° C. and then held at 0° C. for 1 hour.The resultant crystalline solid was collected by suction filtration andpulled dry on the filter. XRPD analysis and the DSC thermogram and TGAtrace showed that the Form 2 ZD1839 MeOH solvate so obtained had about 2equivalents of ZD1839 to about 1 equivalent of methanol, i.e. thematerial was approximately a hemi-solvate.

EXAMPLE 3 Process of Conversion of Form 3 ZD1839 DMSO Solvate to Form 1ZD1839 Polymorph

Form 3 ZD1839 DMSO solvate (from Example 1) was washed with ethylacetate (581 litres). The washed solid was mixed with ethyl acetate (895litres) and the resultant slurry was stirred and heated to 34° C. forabout 1 hour. The mixture was then cooled to 0° C. and held at thattemperature for 2 hours to allow the conversion to proceed. Theresultant solid was separated by filtration, washed with ethyl acetate(580 litres) and dried in a flow of warm nitrogen gas (60° C.). Therewas thus obtained Form 1 ZD1839 polymorph (161 kg) as shown by XRPD andDSC analysis.

EXAMPLE 4 Form 1 ZD1839 Polymorph4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline

Whilst maintaining the temperature of the reaction mixture at about 50°C., phosphorus oxychloride (365 kg) was added to a stirred slurry of7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one(International Patent Application WO 01/04102 within Example 25; 220kg), triethylamine (105 kg) and toluene (1790 litres). The resultantmixture was stirred at about 50° C. for 5 hours to complete theformation of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline.

The resultant stirred slurry was cooled to about 0° C. and isopropanol(527 litres) was added whilst the temperature of the reaction mixturewas maintained between 0° and 5° C. The reaction mass was then warmed toabout 20° C. and held at that temperature for about 1 hour. A solutionof 3-chloro-4-fluoroaniline (168 kg) in isopropanol (228 litres) wasadded and the resultant reaction mixture was stirred and warmed to about66° C. and held at that temperature for about 1 hour. The mixture wasstirred and cooled to about 30° C. and isopropanol (662 litres) andwater (1486 litres) were added in turn. A mixture of aqueous sodiumhydroxide liquor (47% w/w, 755 kg) and water (40 litres) was addedportionwise to the stirred reaction mixture. The resultant mixture waswarmed to about 64° C. and the two liquid phases were allowed toseparate. The lower aqueous layer was run off. The remaining organicphase was initially cooled to about 30° C., warmed to about 50° C. andfinally cooled to about 20° C. at a rate of about 10° C. per hour. Theresultant solid was collected by filtration. The solid so obtained waswashed with isopropanol by preparing a slurry of the material inisopropanol that was stirred for about 30 minutes. The resultant solidwas isolated by filtration. The solid so obtained was washed with ethylacetate by preparing a slurry of the material in ethyl acetate that wasstirred for about 30 minutes. The resultant solid was isolated byfiltration. The ethyl acetate wash was repeated. The resultant solid wasdried with warm nitrogen gas (60° C.). There was thus obtained4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein the form of Form 1 ZD1839 polymorph (224 kg) as shown by XRPD and DSCanalysis.

EXAMPLE 5 Single Crystal X-Ray Data of Form 1 ZD1839 Polymorph

Well-shaped single crystals of Form 1 ZD1839 polymorph were obtained byslow evaporation at ambient temperature of a solution of the compound ofthe Formula I in absolute ethanol. In order to preclude the influence ofair during the data collection, the selected single crystal wasprotected with glue. The X-ray diffraction intensities were collected at200° K using graphite monochromatised MoK(α) radiation and a double-passmethod on a Kappa Charged Coupled Device (CCD) single-crystal X-raydiffractometer equipped with a κ-axis goniometer and an image CCD areadetector (Nonius BV; Kappa-CCD Server Software, Nonius, Delft, TheNetherlands). The diffraction raw data were processed using theDenzo-SMN (Small Molecule Nonius) computer program package, (ZOtwinowski & W Minor, Processing of X-ray Diffraction Data Collected inOscillation Mode, Methods in Enzymology, 1997, 276, 302-326) convertingthe information from the digital image frame to a computer filecontaining h, k and l indices, background and Lp corrected intensitiesof the diffraction spots and estimate of errors. In order to cover thediffraction spots (reflections) within the Ewald sphere, 478 imageframes were recorded with a crystal-camera distance of 35 mm with a stepinterval of 1°. Each frame was irradiated twice in order to discriminatethe spare spots generated by cosmic radiation. Accurate unit-celldimensions were obtained as a result of the real-space vector searchthat indexed reflections. Three linearly independent vectors withminimal determinant (unit-cell volume) were used to define the cellparameters within the Denzo-SMN package. The structure was solved withdirect methods using the SIR92 computer program package for theautomatic solution of crystal structures from X-ray diffraction data (AAltomare, et al., 1992) and refined with full-matrix least-squarestechnique. The refinements were based on F, exploiting the programswithin the MaXus software package (S MacKay et al., 1997 via theChemistry Department, Glasgow University, Scotland; a computer programfor solving, refining and publishing crystal structures from X-raydiffraction data; developed for Mac Science Co., Japan and Nonius, TheNetherlands) and the Platon software package (A Spek et al., 1992, acomputer program developed for the generation and analysis ofstereochemical and molecular geometry data). In the final step of therefinement calculations, all non-hydrogen atoms were allotted withanisotropic thermal displacement factors. The hydrogen atom positionswere calculated geometrically and fixed at relevant positions, 0.96 Åfrom the parent atom. The isotropic displacement factors of all hydrogenatoms were fixed to 0.05 Å². In the full-matrix least squaresrefinements 281 variables were refined against 3184 reflections (with F²₀ >3πF ² _(o)). Further, the final reliability values converged toR=0.0404 and Rw=0.0440. Relevant crystal data together with experimentaldetails and structural refinement parameters are summarised in Table A:1and atomic coordinates are provided in Table A:2. TABLE A:1 Experimentaland Refinement Calculation data for Form 1 ZD1839 polymorph Crystal dataC₂₂H₂₄ClFO₃N₄ MoK(α) radiation: M_(r) = 446.91 λ = 0.71073 Å CrystalSystem: Triclnic Space group: P-1 Unit-cell parameters: average valuesfrom image indexed reflections a = 8.876(1) Å α = 93.51(1)° b = 9.692(1)Å β = 97.36(1)° c = 12.543(1) Å γ = 101.70(1)° V = 1043.6(2) Å³ crystalshape: needle Z = 2 0.14 × 0.14 × 0.29 mm D_(x) = 1.4222(3) Mg m − 3colourless T = 200 K μ = 2.2 cm − 1 hkl-range: −10 < h < 11, −9 < k <12, −16< 1 < 16 F(000) = 468.0 electrons Data collection Nonius BVKappaCCD Diffractometer Number of collected frames: 478 Number ofrepeats: 1 Distance: crystal-detector D_(x) = 35 mm Phi-rotation step 1Exposure time: 15 sec/frame Resolution: 0.66 Å Covered θ-range: 1-27.5Total number of measured reflections: 4646 Number of unique observedreflections, 3184 F² _(o) > 3σ(F² _(o)): Absorption correction: noneExtinction parameter (Zachariasen, 1970) 9.9479 exp −3 Refinement MaXus(1997) (Δ/σ)_(max) = 0.0006 Refinement on F (Δ/σ)_(mean) = 0.0001 R =0.0404 Δρ_(max) = 0.21 e Å⁻³ Rw = 0.0440 Δρ_(min) = −0.22 eÅ⁻³ Weightingscheme: w = 1/(σ² F_(o) ² + (0.0300)F²) Atomic scattering factors: maXus(1997) 281 parameters Atomic displacement factors: non-H atomsanisotropic H atoms U_((iso)) = 0.05 Å²

TABLE A:2 Final Coordinates and Equivalent Isotropic DisplacementParameters of the non-Hydrogen atoms for Form 1 ZD1839 polymorph. Atom xy z U(eqv) [Å²] Cl(19) 0.36275(4) 0.84068(3) 0.42511(2) 0.0619(1) F180.39031(7) 1.08739(6) 0.29892(5) 0.0549(2) O20 0.93090(8) 0.14285(6)−0.02633(5) 0.0390(2) O22 0.86297(7) 0.20079(6) 0.16029(4) 0.0340(2) O291.25684(7) 0.45236(6) 0.64985(4) 0.0370(2) N1 0.75916(9) 0.54835(8)−0.16301(6) 0.0373(3) N3 0.65090(9) 0.69616(7) −0.04568(6) 0.0351(3) N110.62866(9) 0.64913(7) 0.13265(5) 0.0319(3) N26 1.09809(9) 0.28952(7)0.45555(5) 0.0307(3) C2 0.69633(12) 0.65563(10) −0.13936(7) 0.0395(3) C40.67182(10) 0.61580(8) 0.03459(7) 0.0285(3) C5 0.73888(10) 0.49402(8)0.02221(6) 0.0271(3) C6 0.76526(10) 0.40484(8) 0.10497(7) 0.0291(3) C70.83115(10) 0.29184(8) 0.08601(7) 0.0283(3) C8 0.87139(10) 0.26072(9)−0.01814(7) 0.0293(3) C9 0.84831(10) 0.34655(9) −0.09798(7) 0.0312(3)C10 0.78163(10) 0.46535(8) −0.07936(7) 0.0289(3) C12 0.56635(10)0.76385(8) 0.16763(7) 0.0295(3) C13 0.56934(11) 0.88739(9) 0.11619(7)0.0355(3) C14 0.50760(12) 0.99477(9) 0.15990(7) 0.0383(3) C150.44717(11) 0.98025(9) 0.25485(8) 0.0367(3) C16 0.44402(11) 0.85905(9)0.30697(7) 0.0350(3) C17 0.50256(11) 0.75092(9) 0.26345(7) 0.0327(3) C210.97517(12) 0.10326(10) −0.12755(7) 0.0414(3) C23 0.83007(11) 0.23029(9)0.26738(7) 0.0323(3) C24 0.88933(11) 0.12432(9) 0.33581(7) 0.0346(3) C251.06324(12) 0.16967(9) 0.37237(7) 0.0374(3) C27 1.25450(12) 0.37519(10)0.46087(7) 0.0411(3) C28 1.28014(12) 0.49842(10) 0.54589(8) 0.0426(4)C30 1.10343(12) 0.36784(10) 0.64376(7) 0.0413(3) C31 1.07840(11)0.24200(10) 0.56203(7) 0.0381(3)Temperature factor of the form: T = exp[−2π²U], U = U(eqv) where U(eqv)= 1/3 Σ(i)Σ(j){U(ij)a(i)a(j)a(i)a(j)

EXAMPLE 6 Form 5 ZD1839 Trihydrate: Prepared by Slurry Process in aSolvent System Containing Water

A mixture of4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline(1 g; Form 1 ZD1839 polymorph, prepared as described in Example 4),isopropanol (5 ml), toluene (10 ml) and water (5 ml) was stirred as aslurry at room temperature for 18 hours. The resultant crystalline solidwas collected by suction filtration and pulled dry on the filter.Analysis of the XRPD, DSC thermogram and TGA trace on the resultantproduct confirmed the product to be Form 5 ZD1839 trihydrate, whichcontained 1 equivalent of ZD1839 to 3 equivalents of water. Thestoichiometry of the trihydrate was confirmed by single-crystal studiesand Karl Fischer water analysis as described herein.

Using an analogous procedure to that described above, the organicsolvent/co-solvent systems shown in Table 2 were used to prepare Form 5ZD1839 trihydrate: TABLE 2 Example Water Organic solvent Co-solvent 6.110 ml/g isopropanol (5 ml/g) 6.2 10 ml/g isopropanol (10 ml/g) 6.3  1ml/g isopropanol (5 ml/g) ethyl acetate (5 ml/g)“ml/g” in Table 2 refers to the volume of water/solvent per g of4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline

The4-(3′-chloro-4′-fluoroanilino)₇-methoxy-6-(3-morpholinopropoxy)quinazolinestarting material used in Examples 6 may also be prepared using themethods disclosed in International Patent Application WO 96/33980 withinExamples 1 and 10.

EXAMPLE 7 Form 5 ZD1839 Trihydrate: Prepared by Crystallisation from aSolvent System Containing Water

Water (900 ml) and isopropanol (720 ml) were added to4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline(60 g). The mixture was stirred and heated to reflux (approximately 82°C.). Additional isopropanol (90 ml) was added to achieve completedissolution of the solid. The solution was maintained at reflux for afurther 2 hours before cooling to ambient temperature over approximately6 hours. The resulting Form 5 ZD1839 trihydrate was formed ascrystalline needles and isolated by filtration.

Solid collected 65.2 g, 97% as trihydrate, confirmed by XRPD, watercontent was measured to be 10.98% by Karl Fischer titration (10.78%theoretical for trihydrate). Weight loss by TGA was 10.67% occurringbetween 25 and 105° C.

EXAMPLE 8 Form 5 ZD1839 Trihydrate: Large Scale Synthesis

The process in Example 4 was repeated except that following the coolingof the organic phase to about 30° C., warming to about 50° C. andcooling to about 20° C. at a rate of about 10° C. per hour, theresultant solid was collected by filtration. XPD analysis of thematerial collected on the filter showed it was Form 5 ZD1839 trihydrate.Further confirmation that the material obtained was the trihydrate wereprovided by DSC, TGA and Karl Fischer titration.

The Form 5 ZD1839 trihydrate isolated on the filter may be washed with asuitable solvent that will not displace the water of crystallisation,for example cold toluene (suitably at a temperature of 0 to 15° C.). Thewashed Form 5 ZD1839 trihydrate may then be dried under conditions whichdo not drive off the water of crystallisation, for example by drying ata low temperature, for example at ambient temperature.

EXAMPLE 9 Form 5 ZD1839 Trihydrate: Single Crystal Analysis

Well-shaped single crystals of Form 5 ZD1839 trihydrate were obtained byslow evaporation at room temperature from an ethanol and water solutionof4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline.In order to preclude the influence of air during the data collection,the selected single crystal was protected with glue. The X-raydiffraction intensities were collected at 298° K on a Kappa ChargedCoupled Device (CCD) single-crystal X-ray diffractometer equipped withgraphite monochromatised MoK(α) radiation (Nonius BV; Kappa-CCD ServerSoftware, Nonius, Delft, The Netherlands). The single crystal data wasgenerated and analysed using an analogous method to that described inExample 5 except that during collection of the diffraction data in orderto cover the diffraction spots (reflections) within the Ewald sphere,251 image frames were recorded with a crystal-camera distance of 40 mmwith a step interval of 1°. Each frame was irradiated twice, 20sec/frame, in order to discriminate the spare spots generated by cosmicradiation.

Additionally, in the full-matrix least squares refinements variableswere refined against 1504 reflections (with F² _(o)>3πF² _(o)). Further,the final reliability values converged to R=0.0468 and Rw=0.0526.Relevant crystal data together with experimental details and structuralrefinement parameters are summarized in Table B:1 and atomic coordinatesare provided in Table B:2. TABLE B:1 Experimental and RefinementCalculation data for ZD1839 trihydrate Crystal data C₂₂H₂₄ClFO₃N₄ 3H₂OMoK(α) radiation: M_(r) = 446.91 + 54.06 λ = 0.71073 Å Crystal System:Monoclinic Space group: P2₁/c Unit-cell parameters: average values fromimage indexed reflections a = 14.405(1) Å α = 90° b = 24.891(1) Å β =92.18(1)° c = 6.811(1) Å γ = 90° V = 2440.4(4) Å³ crystal shape: needleZ = 4 0.06 × 0.06 × 057 mm D_(x) = 1.364(1) Mg m − 3 colourless T = 298K μ = 2.09 cm⁻¹ hkl-range: −17 < h < 17, −30 < k < 30, −8 < 1 < 8 F(000)= 1056.0 electrons Data collection Nonius BV KappaCCD DiffractometerNumber of collected frames: 251 Number of repeats: 1 Distance:crystal-detector D_(x) = 40 mm Phi-rotation step 1 Exposure time: 20sec/frame Resolution: 0.64 Å Covered θ-range: 1-27.5 Total number ofmeasured reflections: 4909 Number of unique observed reflections, 1504F² _(o) > 3σ(F² _(o)): Absorption correction: none Extinction parameter(Zachariasen, 1970) 14.898 exp⁻³ Refinement MaXus (1997) (Δ/σ)_(max) =0.0003 Refinement on F (Δ/σ)_(mean) = 0.0000 308 parameters/1504reflections R = 0.0468 Δρ_(max) = 0.25 e Å⁻³ Rw = 0.0526 Δρ_(min) =−0.28 eÅ⁻³ Weighting scheme: w = 1/(σ² F_(o) ² + (0.0300)F²) Atomicscattering factors: maXus (1997) Atomic displacement factors: non-Hatoms anisotropic H atoms U_((iso)) = 0.05 Å²

TABLE B:2 Final Coordinates and Equivalent Isotropic DisplacementParameters of the non-Hydrogen atoms for: ZD1839 trihydrate. Atom x y zU(eqv) [Å²] Cl(19) 1.02030(13) 0.20446(10) 0.5962(3) 0.1013(10) F181.0862(3) 0.1382(2) 0.9224(6) 0.103(2) O20 0.2787(3) 0.23699(19)0.8144(5) 0.0504(19) O22 0.3532(3) 0.1444(2) 0.8396(6) 0.0472(17) O290.0649(3) −0.0199(2)   0.2566(8) 0.081(3) N1 0.5742(4) 0.3253(2)0.8980(6) 0.039(2) N3 0.7134(4) 0.2721(3) 0.9225(7) 0.042(2) N110.7091(4) 0.1797(2) 0.9301(6) 0.042(2) N26 0.2218(3) 0.0310(2) 0.4457(7)0.0407(19) C2 0.6650(6) 0.3177(3) 0.9148(8) 0.045(3) C4 0.6632(5)0.2273(3) 0.9166(8) 0.035(3) C5 0.5639(5) 0.2278(3) 0.8976(7) 0.031(3)C6 0.5077(5) 0.1816(3) 0.8838(8) 0.036(3) C7 0.4146(5) 0.1862(3)0.8579(7) 0.034(3) C8 0.3730(5) 0.2381(3) 0.8462(7) 0.036(3) C90.4262(5) 0.2830(3) 0.8622(8) 0.035(3) C10 0.5231(5) 0.2786(3) 0.8872(7)0.035(3) C12 0.8070(5) 0.1726(3) 0.9321(9) 0.042(3) C13 0.8488(5)0.1404(4) 1.0726(10) 0.078(4) C14 0.9421(6) 0.1289(4) 1.0704(11)0.096(5) C15 0.9936(5) 0.1496(3) 0.9271(12) 0.065(4) C16 0.9538(5)0.1812(3) 0.7840(9) 0.051(3) C17 0.8605(5) 0.1934(3) 0.7858(9) 0.050(3)C21 0.2313(5) 0.2874(3) 0.8026(10) 0.064(3) C23 0.3926(5) 0.0922(3)0.8147(9) 0.047(3) C24 0.3155(5) 0.0544(3) 0.7517(8) 0.046(3) C250.2618(5) 0.0745(3) 0.5700(9) 0.048(3) C27 0.1719(5) 0.0544(3)0.2742(10) 0.059(3) C28 0.1270(6) 0.0112(3) 0.1494(10) 0.067(3) C300.1125(6) −0.0437(3)   0.4196(12) 0.077(4) C31 0.1587(5) −0.0024(3)  0.5544(9) 0.058(3) Water molecules O1 0.5321(3) 0.06720(17) 0.3601(6)0.0585(17) O2 0.6433(3) 0.07371(17) 0.0243(6) 0.0629(19) O3 0.3895(3)−0.00947(17)   0.3119(6) 0.0593(19)Temperature factor of the form: T = exp[−2π²U], U = U(eqv) where U(eqv)= 1/3 Σ(i)Σ(j){U(ij)a(i)a(j)a(i)a(j)

EXAMPLE 10 Tablets

Specific examples of tablet formulations of an active substance of theinvention comprising Form 3 ZD1839 DMSO solvate, Form 2 ZD1839 MeOHsolvate or Form 1 ZD1839 polymorph, are described hereinafter. mg/tablet100 mg Tablet Core: active substance 100 Lactose 65.4 MicrocrystallineCellulose 20 Croscarmellose Sodium 8 Polyvidone 4 Sodium Lauryl Sulphate0.6 Magnesium Stearate 2 Coating: Methylhydroxypropylcellulose 3Polyethylene Glycol, PEG 300 0.6 Titanium Dioxide 0.2 250 mg Tablet Coreactive substance 250 Lactose 163.5 Microcrystalline Cellulose 50Croscarmellose Sodium 20 Polyvidone 10 Sodium Lauryl Sulphate 1.5Magnesium Stearate 5 Coating: Methylhydroxypropylcellulose 7.6Polyethylene Glycol, PEG 300 1.5 Titanium Dioxide 0.5

EXAMPLE 11 Aqueous Suspension

The following aqueous suspensions of Form 5 ZD1839 trihydrate may beprepared as described below:

Aqueous Suspension A:

-   20 mg/ml concentration Form 5 ZD1839 trihydrate in water;-   0.2% Polysorbate 20;-   pH 7 phosphate buffer; and-   0.9% NaCl    Aqueous Suspension B-   10 mg/ml concentration Form 5 ZD1839 trihydrate in water;-   0.2% Polysorbate 20;-   pH 7 phosphate buffer; and-   0.9% NaCl;    wherein % are by weight

Micronised Form 5 ZD1839 trihydrate is added to a solution of thePolysorbate in the phosphate buffer solution. The resulting mixture ismixed using a homogeniser to give a smooth suspension. The suspension isadded to a solution of the sodium chloride in phosphate buffer and thesuspension is mixed by stirring. Additional phosphate buffer is; addedto give the required concentration of Form 5 ZD1839 trihydrate in thesuspension. The pH phosphate buffer used in the suspension formulationsmay be prepared by dissolving monobasic sodium phosphate (NaH₂PO₄; 17.3mg/ml (1.73 weight %)) and dibasic sodium phosphate (Na₂HPO₄; 9.36 mg/ml(0.94 weight %)) in sterile purified water.

Both suspensions are stable during prolonged storage at ambienttemperature.

1. A crystalline form of the compound of the Formula I substantially inthe form of Form 3 ZD1839 DMSO solvate.
 2. The solvate according toclaim 1 characterised by an X-ray diffraction pattern havingcharacterising peaks at about 8.9, 17.8, 22.6 and 23.20 on the 20 scale.3. The solvate according to claim 1 characterised by an X-raydiffraction pattern substantially as shown in FIG.
 7. 4. The solvateaccording to claim 1 characterised by a desolvation point in the rangeof about 127° C. to 132° C.
 5. The solvate according to claim 1characterised by one or both of the Differential Scanning Calorimetrythermogram and Thermal Gravimetric Analysis trace substantially as shownin FIG.
 8. 6. The solvate according to claim 1 characterised by aDiffuse Reflectance Infrared Fourier Transform spectrum withdistinguishing peaks at about 1640, 1520, 1450, 880 and 560 cm⁻¹.
 7. Thesolvate according to claim 1 characterised by a Diffuse ReflectanceInfrared Fourier Transform spectrum substantially as shown in FIG.
 9. 8.A crystalline form of the compound of the Formula I substantially in theform of Form 3 ZD1839 DMSO solvate according to claim 1 which issubstantially free of any other ZD1839 solvate or any Form 1 ZD1839polymorph.
 9. A process for preparing a crystalline form of the compoundof the Formula I substantially in the form of Form 3 ZD1839 DMSO solvateaccording to claim 1 which comprises:— (a) heating a mixture of thecompound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein dimethyl sulphoxide or a solvent mixture containing dimethylsulphoxide and a co-solvent until dissolution has occurred; (b) reducingthe temperature of the solvent system to induce nucleation; (c)maintaining the mixture at a temperature below that at which nucleationhas commenced; and (d) isolating the crystalline solid so deposited. 10.A crystalline form of the compound of the Formula I substantially in theform of Form 2 ZD1839 MeOH solvate.
 11. The solvate according to claim10 characterised by an X-ray diffraction pattern having characterisingpeaks at about 6.5, 10.0 and 13.2° on the 20 scale.
 12. The solvateaccording to claim 10 characterised by an X-ray diffraction patternsubstantially as shown in FIG.
 4. 13. The solvate according to claim 10characterised by a desolvation point in the range of about 125° C. to130° C.
 14. The solvate according to claim 10 characterised by one orboth of the Differential Scanning Calorimetry thermogram and ThermalGravimetric Analysis trace substantially as shown in FIG.
 5. 15. Thesolvate according to claim 10 characterised by a Diffuse ReflectanceInfrared Fourier Transform spectrum with distinguishing peaks at about3380, 1650, 1530, 1450, 1235, 870 and 570 cm^(−1.)
 16. The solvateaccording to claim 10 characterised by a Diffuse Reflectance InfraredFourier Transform spectrum substantially as shown in FIG.
 6. 17. Acrystalline form of the compound of the Formula I substantially in theform of Form 2 ZD1839 MeOH solvate according to claim 10 which issubstantially free of any other ZD1839 solvate or any Form 1 ZD1839polymorph.
 18. A process for preparing a crystalline form of thecompound of the Formula I substantially in the form of Form 2 ZD1839MeOH solvate according to claim 10 which comprises:— (a) heating amixture of the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein methanol or a solvent mixture containing methanol and a co-solventuntil dissolution has occurred; (b) reducing the temperature of thesolvent system to induce nucleation; (c) maintaining the mixture at atemperature below that at which nucleation has commenced; and (d)isolating the crystalline solid so deposited.
 19. A process for thepreparation of the compound of Formula I substantially in the form ofForm 1 ZD1839 polymorph which comprises:— (a) washing Form 3 ZD1839 DMSOsolvate according to claim 1 with a solvent or solvent mixturesubstantially to remove dimethyl sulphoxide; and (b) isolating the Form1 ZD1839 polymorph so formed.
 20. A process for the preparation of thecompound of Formula I substantially in the form of Form 1 ZD1839polymorph which comprises:— (a) washing Form 2 ZD1839 MeOH solvateaccording to claim 10 with a solvent or solvent mixture substantially toremove methanol; and (b) isolating the Form 1 ZD1839 polymorph soformed.
 21. A compound of the Formula I substantially in the form ofForm 5 ZD1839 trihydrate.
 22. The Form 5 ZD1839 trihydrate according toclaim 21 characterised by an X-ray diffraction pattern havingcharacterising peaks at about 6.1, 7.1 and 25.7° on the 20 scale. 23.The Form 5 ZD1839 trihydrate according to claim 21 characterised by anX-ray diffraction pattern having characterising peaks at about 6.1, 7.1,9.3, 14.2, 18.5, 18.8, 19.8, 22.3, 23.3, 24.7 and 25.70 on the 20 scale.24. The Form 5 ZD1839 trihydrate according to claim 21 characterised byan X-ray diffraction pattern substantially as shown in FIG.
 10. 25. TheForm 5 ZD1839 trihydrate according to claim 21 characterised by aDifferential Scanning Calorimetry thermogram having a first endothermwith a peak at approximately 100° C. and a second endotherm with a peakat approximately 194° C. to 198° C.
 26. The Form 5 ZD1839 trihydrateaccording to claim 21 characterised by one or both of the DifferentialScanning Calorimetry thermogram and Thermal Gravimetric Analysis tracesubstantially as shown in FIG.
 11. 27. The Form 5 ZD1839 trihydrateaccording to claim 21 which is substantially free of any other ZD1839solvate or any other crystalline Form of ZD1839.
 28. The Form 5 ZD1839trihydrate according to any one of claims 21 to 27 which is highlycrystalline.
 29. A process for preparing a compound of the Formula Isubstantially in the form of Form ZD1839 trihydrate according to claim21 which comprises:— (a) contacting4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinewith water for a sufficient time to convert the4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineto the Form 5 trihydrate; and (b) isolating the Form 5 ZD1839trihydrate.
 30. A process for crystallising a compound of the Formula Isubstantially in the form of Form 5 ZD1839 trihydrate according to claim21 which comprises the steps:— (a) dissolving the compound4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolinein a solvent system comprising water and an organic solvent; (b)reducing the temperature of the solvent system to induce nucleation; (c)maintaining the mixture at a temperature below that at which nucleationhas commenced; and (d) isolating the crystalline Form 5 ZD1839trihydrate.
 31. A process for the preparation of a compound of Formula Isubstantially in the form of Form 1 ZD1839 polymorph which comprises:(a) washing a compound of Formula I substantially in the form of Form 5ZD1839 trihydrate as defined in claim 21 with a solvent or solventmixture substantially to remove water; and (b) isolating the Form 1ZD1839 polymorph so formed.
 32. A process for the preparation of thecompound of Formula I substantially in the form of Form 1 ZD1839polymorph which comprises heating a compound of Formula I substantiallyin the form of Form 5 ZD1839 trihydrate for a sufficient time and atsufficient temperature to drive off water and effect transformation toForm 1 ZD1839 polymorph.
 33. A pharmaceutical composition whichcomprises the crystalline form of the compound of the Formula Iaccording to any one of claims 1, 10 or 21 and apharmaceutically-acceptable diluent or carrier.
 34. A pharmaceuticalcomposition according to claim 33 that is adapted for oraladministration.
 35. A pharmaceutical composition according to claim 33which comprises a suspension of a compound of Formula I substantially inthe form of Form 5 ZD1839 trihydrate as defined in claim 21 in anaqueous medium.